|
Inhibition of c-Met (unknown origin)
|
Homo sapiens
|
21.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety as potential antitumor agents.
Year : 2014
Volume : 83
First Page : 581
Last Page : 593
Authors : Zhou S, Liao H, He C, Dou Y, Jiang M, Ren L, Zhao Y, Gong P.
Abstract : A series of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (HT-29, H460, A549, MKN-45, and U87MG). Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines. Compounds 15a, 20a, 15b, 15c, 20d, and 16e were further examined for their inhibitory activity against c-Met kinase. The most promising compound 15a (c-Met half-maximal inhibitory concentration [IC50] = 2.15 nM) showed remarkable cytotoxicity against HT-29, H460, and A549 cell lines with IC50 values of 0.10 μM, 0.13 μM, and 0.05 μM, respectively, and thus it was 1.5- to 2.3-fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.
|
Inhibition of VEGFR2 (unknown origin)
|
Homo sapiens
|
7.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety as potential antitumor agents.
Year : 2014
Volume : 83
First Page : 581
Last Page : 593
Authors : Zhou S, Liao H, He C, Dou Y, Jiang M, Ren L, Zhao Y, Gong P.
Abstract : A series of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (HT-29, H460, A549, MKN-45, and U87MG). Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines. Compounds 15a, 20a, 15b, 15c, 20d, and 16e were further examined for their inhibitory activity against c-Met kinase. The most promising compound 15a (c-Met half-maximal inhibitory concentration [IC50] = 2.15 nM) showed remarkable cytotoxicity against HT-29, H460, and A549 cell lines with IC50 values of 0.10 μM, 0.13 μM, and 0.05 μM, respectively, and thus it was 1.5- to 2.3-fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.
|
Inhibition of RON (unknown origin) at 0.1 uM by ELISA method
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent 1H-imidazo[4,5-b]pyridine-based c-Met kinase inhibitors via mechanism-directed structural optimization.
Year : 2015
Volume : 25
Issue : 3
First Page : 708
Last Page : 716
Authors : An XD, Liu H, Xu ZL, Jin Y, Peng X, Yao YM, Geng M, Long YQ.
Abstract : Starting from our previously identified novel c-Met kinase inhibitors bearing 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one scaffold, a global structural exploration was conducted to furnish an optimal binding motif for further development, directed by the enzyme inhibitory mechanism. First round SAR study picked two imidazonaphthyridinone frameworks with 1,8- and 3,5-disubstitution pattern as class I and class II c-Met kinase inhibitors, respectively. Further structural optimization on type II inhibitors by truncation of the imidazonaphthyridinone core and incorporation of an N-phenyl cyclopropane-1,1-dicarboxamide pharmacophore led to the discovery of novel imidazopyridine-based c-Met kinase inhibitors, displaying nanomolar enzyme inhibitory activity and improved Met kinase selectivity. More significantly, the new chemotype c-Met kinase inhibitors effectively inhibited Met phosphorylation and its downstream signaling as well as the proliferation of Met-dependent EBC-1 human lung cancer cells at submicromolar concentrations.
|
Inhibition of AXL (unknown origin) at 0.1 uM by ELISA method
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent 1H-imidazo[4,5-b]pyridine-based c-Met kinase inhibitors via mechanism-directed structural optimization.
Year : 2015
Volume : 25
Issue : 3
First Page : 708
Last Page : 716
Authors : An XD, Liu H, Xu ZL, Jin Y, Peng X, Yao YM, Geng M, Long YQ.
Abstract : Starting from our previously identified novel c-Met kinase inhibitors bearing 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one scaffold, a global structural exploration was conducted to furnish an optimal binding motif for further development, directed by the enzyme inhibitory mechanism. First round SAR study picked two imidazonaphthyridinone frameworks with 1,8- and 3,5-disubstitution pattern as class I and class II c-Met kinase inhibitors, respectively. Further structural optimization on type II inhibitors by truncation of the imidazonaphthyridinone core and incorporation of an N-phenyl cyclopropane-1,1-dicarboxamide pharmacophore led to the discovery of novel imidazopyridine-based c-Met kinase inhibitors, displaying nanomolar enzyme inhibitory activity and improved Met kinase selectivity. More significantly, the new chemotype c-Met kinase inhibitors effectively inhibited Met phosphorylation and its downstream signaling as well as the proliferation of Met-dependent EBC-1 human lung cancer cells at submicromolar concentrations.
|
Inhibition of recombinant MET kinase domain (unknown origin)
|
Homo sapiens
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of highly selective pyridone-based class II MET inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3351
Last Page : 3355
Authors : She N, Zhuo L, Jiang W, Zhu X, Wang J, Ming Z, Zhao X, Cong X, Huang W.
Abstract : The high incidence of MET oncogene activation in human malignancies has prompted researchers to develop MET inhibitors. As part of our efforts to developing effective and safe therapeutic agents against MET-dependent tumors, a pyridone-based class II MET inhibitor, namely, 1-(4-((2-amino-3-iodopyridin-4-yl)-oxy)-3-fluorophenyl)-N-(4-fluorobenzyl)-4-methoxy-6-oxo-1,6-dihydropyridine-3-carboxamide (3s), was identified. Knowledge of the binding mode of class II MET inhibitors led to the design of new inhibitors that utilize 2-pyridone to conformationally restrain key pharmacophoric groups within the molecule. Integrated molecular docking and SAR studies resulted in the discovery of a novel class of pyridone MET inhibitors with high potency (IC50 of 0.005 μM) and efficient selectivity (>5000 fold) to VEGFR-2, c-Kit and RET kinases.
|
Inhibition of recombinant VEGFR2 kinase domain (unknown origin)
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of highly selective pyridone-based class II MET inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3351
Last Page : 3355
Authors : She N, Zhuo L, Jiang W, Zhu X, Wang J, Ming Z, Zhao X, Cong X, Huang W.
Abstract : The high incidence of MET oncogene activation in human malignancies has prompted researchers to develop MET inhibitors. As part of our efforts to developing effective and safe therapeutic agents against MET-dependent tumors, a pyridone-based class II MET inhibitor, namely, 1-(4-((2-amino-3-iodopyridin-4-yl)-oxy)-3-fluorophenyl)-N-(4-fluorobenzyl)-4-methoxy-6-oxo-1,6-dihydropyridine-3-carboxamide (3s), was identified. Knowledge of the binding mode of class II MET inhibitors led to the design of new inhibitors that utilize 2-pyridone to conformationally restrain key pharmacophoric groups within the molecule. Integrated molecular docking and SAR studies resulted in the discovery of a novel class of pyridone MET inhibitors with high potency (IC50 of 0.005 μM) and efficient selectivity (>5000 fold) to VEGFR-2, c-Kit and RET kinases.
|
Inhibition of c-Kit (unknown origin)
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of highly selective pyridone-based class II MET inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3351
Last Page : 3355
Authors : She N, Zhuo L, Jiang W, Zhu X, Wang J, Ming Z, Zhao X, Cong X, Huang W.
Abstract : The high incidence of MET oncogene activation in human malignancies has prompted researchers to develop MET inhibitors. As part of our efforts to developing effective and safe therapeutic agents against MET-dependent tumors, a pyridone-based class II MET inhibitor, namely, 1-(4-((2-amino-3-iodopyridin-4-yl)-oxy)-3-fluorophenyl)-N-(4-fluorobenzyl)-4-methoxy-6-oxo-1,6-dihydropyridine-3-carboxamide (3s), was identified. Knowledge of the binding mode of class II MET inhibitors led to the design of new inhibitors that utilize 2-pyridone to conformationally restrain key pharmacophoric groups within the molecule. Integrated molecular docking and SAR studies resulted in the discovery of a novel class of pyridone MET inhibitors with high potency (IC50 of 0.005 μM) and efficient selectivity (>5000 fold) to VEGFR-2, c-Kit and RET kinases.
|
Inhibition of RET (unknown origin)
|
Homo sapiens
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of highly selective pyridone-based class II MET inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3351
Last Page : 3355
Authors : She N, Zhuo L, Jiang W, Zhu X, Wang J, Ming Z, Zhao X, Cong X, Huang W.
Abstract : The high incidence of MET oncogene activation in human malignancies has prompted researchers to develop MET inhibitors. As part of our efforts to developing effective and safe therapeutic agents against MET-dependent tumors, a pyridone-based class II MET inhibitor, namely, 1-(4-((2-amino-3-iodopyridin-4-yl)-oxy)-3-fluorophenyl)-N-(4-fluorobenzyl)-4-methoxy-6-oxo-1,6-dihydropyridine-3-carboxamide (3s), was identified. Knowledge of the binding mode of class II MET inhibitors led to the design of new inhibitors that utilize 2-pyridone to conformationally restrain key pharmacophoric groups within the molecule. Integrated molecular docking and SAR studies resulted in the discovery of a novel class of pyridone MET inhibitors with high potency (IC50 of 0.005 μM) and efficient selectivity (>5000 fold) to VEGFR-2, c-Kit and RET kinases.
|
Inhibition of purified recombinant c-MET (unknown origin) using poly (Glu, Tyr) substrate after 60 mins by ELISA
|
Homo sapiens
|
3.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold.
Year : 2015
Volume : 23
Issue : 3
First Page : 564
Last Page : 578
Authors : Jiang X, Liu H, Song Z, Peng X, Ji Y, Yao Q, Geng M, Ai J, Zhang A.
Abstract : A series of 3-amino-benzo[d]isoxazole-/3-aminoindazole-based compounds were designed, synthesized and pharmacologically evaluated as tyrosine kinase c-Met inhibitors. The SAR study was conducted leading to identification of nine compounds (8d, 8e, 12, 28a-d, 28h and 28i) with IC50s less than 10nM against c-Met. Compound 28a stood out as the most potent c-Met inhibitor displaying potent inhibitory effects both at enzymatic (IC50=1.8 nM) and cellular (IC50=0.18 μM on EBC-1 cells) levels. In addition, 28a had a relatively good selectivity compared to a panel of our in-house 14 RTKs.
|
Inhibition of RET (unknown origin)
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Progress in Discovery of KIF5B-RET Kinase Inhibitors for the Treatment of Non-Small-Cell Lung Cancer.
Year : 2015
Volume : 58
Issue : 9
First Page : 3672
Last Page : 3681
Authors : Song M.
Abstract : A new chimeric fusion transcript of KIF5B (the kinesin family 5B gene) and the RET (Rearranged during Transcription) oncogene, KIF5B-RET, was found in 1-2% of lung adenocarcinomas (LADCs) in late 2011. Several related clinical trials for non-small-cell lung cancer (NSCLC) with KIF5B-RET rearrangements using existing RET inhibitors, such as lenvatinib, vandetanib, sunitinib, ponatinib, cabozantinib, and AUY922, have been swiftly initiated by the discovery of the KIF5B-RET fusion gene. Anti-RET activity and the status of clinical development of these known RET tyrosine kinase inhibitors (TKIs) for KIF5B-RET fusion-positive NSCLC are discussed. A kinase inhibitor that can target a driver mutation specifically may lead to a superior clinical benefit compared with broad-spectrum kinase inhibitors. In this regard, an analysis of the structure of RET kinase and its complex with known RET inhibitors are also briefly discussed.
|
Inhibition of human Ret V804M mutant by radiometric assay in presence of [gamma-33P]-ATP
|
Homo sapiens
|
358.0
nM
|
|
Journal : J. Med. Chem.
Title : A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants.
Year : 2016
Volume : 59
Issue : 1
First Page : 358
Last Page : 373
Authors : Yoon H, Kwak Y, Choi S, Cho H, Kim ND, Sim T.
Abstract : Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.
|
Inhibition of human Ret G691S mutant by radiometric assay in presence of [gamma-33P]-ATP
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants.
Year : 2016
Volume : 59
Issue : 1
First Page : 358
Last Page : 373
Authors : Yoon H, Kwak Y, Choi S, Cho H, Kim ND, Sim T.
Abstract : Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.
|
Inhibition of human Ret Y791F mutant by radiometric assay in presence of [gamma-33P]-ATP
|
Homo sapiens
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants.
Year : 2016
Volume : 59
Issue : 1
First Page : 358
Last Page : 373
Authors : Yoon H, Kwak Y, Choi S, Cho H, Kim ND, Sim T.
Abstract : Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.
|
Inhibition of human Ret V804L mutant by radiometric assay in presence of [gamma-33P]-ATP
|
Homo sapiens
|
230.0
nM
|
|
Journal : J. Med. Chem.
Title : A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants.
Year : 2016
Volume : 59
Issue : 1
First Page : 358
Last Page : 373
Authors : Yoon H, Kwak Y, Choi S, Cho H, Kim ND, Sim T.
Abstract : Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.
|
Inhibition of human Ret S891A mutant by radiometric assay in presence of [gamma-33P]-ATP
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants.
Year : 2016
Volume : 59
Issue : 1
First Page : 358
Last Page : 373
Authors : Yoon H, Kwak Y, Choi S, Cho H, Kim ND, Sim T.
Abstract : Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.
|
Inhibition of human Ret M918T mutant by radiometric assay in presence of [gamma-33P]-ATP
|
Homo sapiens
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants.
Year : 2016
Volume : 59
Issue : 1
First Page : 358
Last Page : 373
Authors : Yoon H, Kwak Y, Choi S, Cho H, Kim ND, Sim T.
Abstract : Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.
|
Inhibition of human RET using poly(Glu, Tyr) as substrate by Luciferase-Coupled Chemiluminescence assay
|
Homo sapiens
|
5.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.
Year : 2016
Volume : 108
First Page : 495
Last Page : 504
Authors : Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L.
Abstract : Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
|
Inhibition of human KIT using poly(Glu, Tyr) as substrate by AlphaScreen assay
|
Homo sapiens
|
4.6
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.
Year : 2016
Volume : 108
First Page : 495
Last Page : 504
Authors : Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L.
Abstract : Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
|
Inhibition of human c-Met using poly(Glu, Tyr) as substrate by Luciferase-Coupled Chemiluminescence assay
|
Homo sapiens
|
1.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.
Year : 2016
Volume : 108
First Page : 495
Last Page : 504
Authors : Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L.
Abstract : Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
|
Inhibition of human VEGFR-2 using poly(Glu, Tyr) as substrate by AlphaScreen assay
|
Homo sapiens
|
0.035
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.
Year : 2016
Volume : 108
First Page : 495
Last Page : 504
Authors : Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L.
Abstract : Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
|
Inhibition of human TIE2 using poly(Glu, Tyr) as substrate by [33P]-phosphoryl transfer assay
|
Homo sapiens
|
14.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.
Year : 2016
Volume : 108
First Page : 495
Last Page : 504
Authors : Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L.
Abstract : Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
|
Inhibition of human FLT3 using poly(Glu, Tyr) as substrate by Luciferase-Coupled Chemiluminescence assay
|
Homo sapiens
|
11.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.
Year : 2016
Volume : 108
First Page : 495
Last Page : 504
Authors : Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L.
Abstract : Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
|
Inhibition of human AXL using poly(Glu, Tyr) as substrate
|
Homo sapiens
|
7.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.
Year : 2016
Volume : 108
First Page : 495
Last Page : 504
Authors : Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L.
Abstract : Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
|
Inhibition of human RET cytoplasmic domain (658 to 1114 residues) expressed in baculovirus system preincubated for 15 mins followed by substrate addition measured after 20 mins by HTRF assay
|
Homo sapiens
|
650.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
Year : 2016
Volume : 112
First Page : 20
Last Page : 32
Authors : Newton R, Bowler KA, Burns EM, Chapman PJ, Fairweather EE, Fritzl SJ, Goldberg KM, Hamilton NM, Holt SV, Hopkins GV, Jones SD, Jordan AM, Lyons AJ, Nikki March H, McDonald NQ, Maguire LA, Mould DP, Purkiss AG, Small HF, Stowell AI, Thomson GJ, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ.
Abstract : Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
|
Inhibition of recombinant His-tagged human KDR expressed in insect Sf21 cells preincubated for 15 mins followed by substrate addition measured after 20 mins by HTRF assay
|
Homo sapiens
|
16.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
Year : 2016
Volume : 112
First Page : 20
Last Page : 32
Authors : Newton R, Bowler KA, Burns EM, Chapman PJ, Fairweather EE, Fritzl SJ, Goldberg KM, Hamilton NM, Holt SV, Hopkins GV, Jones SD, Jordan AM, Lyons AJ, Nikki March H, McDonald NQ, Maguire LA, Mould DP, Purkiss AG, Small HF, Stowell AI, Thomson GJ, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ.
Abstract : Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
|
Inhibition of KIF5B/RET (unknown origin) expressed in mouse BA/F3 cells assessed as reduction in cell viability after 48 hrs by Cell titre glo-based luminescence assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
Year : 2016
Volume : 112
First Page : 20
Last Page : 32
Authors : Newton R, Bowler KA, Burns EM, Chapman PJ, Fairweather EE, Fritzl SJ, Goldberg KM, Hamilton NM, Holt SV, Hopkins GV, Jones SD, Jordan AM, Lyons AJ, Nikki March H, McDonald NQ, Maguire LA, Mould DP, Purkiss AG, Small HF, Stowell AI, Thomson GJ, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ.
Abstract : Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
|
Inhibition of KDR (unknown origin) expressed in mouse BA/F3 cells assessed as reduction in cell viability after 48 hrs by Cell titre glo-based luminescence assay
|
Homo sapiens
|
14.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
Year : 2016
Volume : 112
First Page : 20
Last Page : 32
Authors : Newton R, Bowler KA, Burns EM, Chapman PJ, Fairweather EE, Fritzl SJ, Goldberg KM, Hamilton NM, Holt SV, Hopkins GV, Jones SD, Jordan AM, Lyons AJ, Nikki March H, McDonald NQ, Maguire LA, Mould DP, Purkiss AG, Small HF, Stowell AI, Thomson GJ, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ.
Abstract : Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
|
Antiproliferative activity against mouse BA/F3 cells expressing TPR-Met after 72 hrs by CCK8 assay
|
Mus musculus
|
21.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2.
Year : 2016
Volume : 24
Issue : 16
First Page : 3353
Last Page : 3358
Authors : Qiang H, Gu W, Huang D, Shi W, Qiu Q, Dai Y, Huang W, Qian H.
Abstract : The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210nM and 170nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
|
Inhibition of recombinant c-Met (unknown origin) using poly (Glu, Tyr) 4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
3.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2.
Year : 2016
Volume : 24
Issue : 16
First Page : 3353
Last Page : 3358
Authors : Qiang H, Gu W, Huang D, Shi W, Qiu Q, Dai Y, Huang W, Qian H.
Abstract : The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210nM and 170nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
|
Inhibition of recombinant VEGFR2 (unknown origin) using poly (Glu, Tyr) 4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2.
Year : 2016
Volume : 24
Issue : 16
First Page : 3353
Last Page : 3358
Authors : Qiang H, Gu W, Huang D, Shi W, Qiu Q, Dai Y, Huang W, Qian H.
Abstract : The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210nM and 170nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
|
Inhibition of full length recombinant human GST or His-tagged c-Met using poly (Glu, Tyr) as substrate by luciferase coupled chemiluminescence assay
|
Homo sapiens
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2.
Year : 2016
Volume : 24
Issue : 16
First Page : 3353
Last Page : 3358
Authors : Qiang H, Gu W, Huang D, Shi W, Qiu Q, Dai Y, Huang W, Qian H.
Abstract : The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210nM and 170nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
|
Inhibition of full length recombinant human GST or His-tagged VEGFR2 using poly (Glu, Tyr) as substrate by AlphaScreen assay
|
Homo sapiens
|
0.035
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2.
Year : 2016
Volume : 24
Issue : 16
First Page : 3353
Last Page : 3358
Authors : Qiang H, Gu W, Huang D, Shi W, Qiu Q, Dai Y, Huang W, Qian H.
Abstract : The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210nM and 170nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
|
Inhibition of wild type N-terminal GST-tagged recombinant human RET (658 residues) expressed in insect Sf21 cells using poly(Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
3.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : An orally available tyrosine kinase ALK and RET dual inhibitor bearing the tetracyclic benzo[b]carbazolone core.
Year : 2016
Volume : 118
First Page : 244
Last Page : 249
Authors : Song Z, Xia Z, Ji Y, Xing L, Gao Y, Ai J, Geng M, Zhang A.
Abstract : Our early structure-activity relationship study has identified benzo[b]carbazolone 6 as a high potency orally bioavailable ALK inhibitor. Further lead profiling disclosed that 6 is active against both ALK resistant and hot spot-activating mutants, and is also highly potent against RET kinase. Tumor stasis and partial tumor regression were achieved with 6 in both NIH/3T3-EML4-ALK and NIH/3T3-EML4-ALK L1196M xenograft models. Based on the optimal in vitro and in vivo antitumor efficacy, compound 6 is now being profiled further in our preclinical settings as a new orally available ALK/RET dual inhibitor.
|
Inhibition of N-terminal GST-tagged recombinant human RET V804M mutant (658 residues) expressed in insect Sf21 cells using poly(Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
811.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : An orally available tyrosine kinase ALK and RET dual inhibitor bearing the tetracyclic benzo[b]carbazolone core.
Year : 2016
Volume : 118
First Page : 244
Last Page : 249
Authors : Song Z, Xia Z, Ji Y, Xing L, Gao Y, Ai J, Geng M, Zhang A.
Abstract : Our early structure-activity relationship study has identified benzo[b]carbazolone 6 as a high potency orally bioavailable ALK inhibitor. Further lead profiling disclosed that 6 is active against both ALK resistant and hot spot-activating mutants, and is also highly potent against RET kinase. Tumor stasis and partial tumor regression were achieved with 6 in both NIH/3T3-EML4-ALK and NIH/3T3-EML4-ALK L1196M xenograft models. Based on the optimal in vitro and in vivo antitumor efficacy, compound 6 is now being profiled further in our preclinical settings as a new orally available ALK/RET dual inhibitor.
|
Inhibition of CCDC6-RET (unknown origin) expressed in mouse BaF3 cells assessed as inhibition of cell proliferation after 72 hrs by SRB/CCK-8 assay
|
Homo sapiens
|
889.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : An orally available tyrosine kinase ALK and RET dual inhibitor bearing the tetracyclic benzo[b]carbazolone core.
Year : 2016
Volume : 118
First Page : 244
Last Page : 249
Authors : Song Z, Xia Z, Ji Y, Xing L, Gao Y, Ai J, Geng M, Zhang A.
Abstract : Our early structure-activity relationship study has identified benzo[b]carbazolone 6 as a high potency orally bioavailable ALK inhibitor. Further lead profiling disclosed that 6 is active against both ALK resistant and hot spot-activating mutants, and is also highly potent against RET kinase. Tumor stasis and partial tumor regression were achieved with 6 in both NIH/3T3-EML4-ALK and NIH/3T3-EML4-ALK L1196M xenograft models. Based on the optimal in vitro and in vivo antitumor efficacy, compound 6 is now being profiled further in our preclinical settings as a new orally available ALK/RET dual inhibitor.
|
Inhibition of VEGFR2 (unknown origin)
|
Homo sapiens
|
0.035
nM
|
|
Journal : J Med Chem
Title : The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.
Year : 2016
Volume : 59
Issue : 19
First Page : 8712
Last Page : 8756
Authors : Talele TT.
Abstract : Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,
|
Inhibition of MET (unknown origin)
|
Homo sapiens
|
1.3
nM
|
|
Journal : J Med Chem
Title : The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.
Year : 2016
Volume : 59
Issue : 19
First Page : 8712
Last Page : 8756
Authors : Talele TT.
Abstract : Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,
|
Inhibition of RET (unknown origin)
|
Homo sapiens
|
4.0
nM
|
|
Journal : J Med Chem
Title : The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.
Year : 2016
Volume : 59
Issue : 19
First Page : 8712
Last Page : 8756
Authors : Talele TT.
Abstract : Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,
|
Inhibition of KIT (unknown origin)
|
Homo sapiens
|
4.6
nM
|
|
Journal : J Med Chem
Title : The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.
Year : 2016
Volume : 59
Issue : 19
First Page : 8712
Last Page : 8756
Authors : Talele TT.
Abstract : Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,
|
Inhibition of FLT1 (unknown origin)
|
Homo sapiens
|
12.0
nM
|
|
Journal : J Med Chem
Title : The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.
Year : 2016
Volume : 59
Issue : 19
First Page : 8712
Last Page : 8756
Authors : Talele TT.
Abstract : Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,
|
Inhibition of FLT2 (unknown origin)
|
Homo sapiens
|
11.3
nM
|
|
Journal : J Med Chem
Title : The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.
Year : 2016
Volume : 59
Issue : 19
First Page : 8712
Last Page : 8756
Authors : Talele TT.
Abstract : Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,
|
Inhibition of FLT3 (unknown origin)
|
Homo sapiens
|
6.0
nM
|
|
Journal : J Med Chem
Title : The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.
Year : 2016
Volume : 59
Issue : 19
First Page : 8712
Last Page : 8756
Authors : Talele TT.
Abstract : Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,
|
Inhibition of TIE-2 (unknown origin)
|
Homo sapiens
|
14.3
nM
|
|
Journal : J Med Chem
Title : The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.
Year : 2016
Volume : 59
Issue : 19
First Page : 8712
Last Page : 8756
Authors : Talele TT.
Abstract : Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,
|
Inhibition of AXL (unknown origin)
|
Homo sapiens
|
7.0
nM
|
|
Journal : J Med Chem
Title : The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.
Year : 2016
Volume : 59
Issue : 19
First Page : 8712
Last Page : 8756
Authors : Talele TT.
Abstract : Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
918.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
342.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
209.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
501.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
746.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
53.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
560.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
86.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
767.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Inhibition of recombinant c-MET (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 45 mins by ELISA
|
Homo sapiens
|
2.9
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Antiproliferative activity against human HepG2 cells after 72 hrs by MTT assay
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Antiproliferative activity against human EBC1 cells after 72 hrs by MTT assay
|
Homo sapiens
|
51.4
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of EGFR (unknown origin) by HTRF method
|
Homo sapiens
|
225.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of FLT3 (unknown origin) by HTRF method
|
Homo sapiens
|
25.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of VEGFR-2 (unknown origin) by HTRF method
|
Homo sapiens
|
0.086
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of KIT (unknown origin) by HTRF method
|
Homo sapiens
|
6.6
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of RET (unknown origin) by HTRF method
|
Homo sapiens
|
10.1
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of c-MET (unknown origin)
|
Homo sapiens
|
1.3
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of VEGFR-2 (unknown origin)
|
Homo sapiens
|
0.035
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of Ret (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
2.4
nM
|
|
Journal : Eur J Med Chem
Title : The discovery of novel benzothiazinones as highly selective non-ATP competitive glycogen synthase kinase 3β inhibitors for the treatment of ovarian cancer.
Year : 2017
Volume : 135
First Page : 370
Last Page : 381
Authors : Gao Y, Ye DY, Zhou WC, Chu Y.
Abstract : Glycogen synthase kinase 3β (GSK 3β) is a highly conserved serine/threonine kinase, and its roles in cancer remain controversial. Cumulative evidence supported that GSK 3β inhibitors could suppress ovarian cancer (OC) development in vitro and made a new direction for ovarian cancer treatment. Here, we reported a series of novel substituted benzothiazinones as non-ATP competitive inhibitors of GSK 3β. Further studies showed that most of them had antiproliferative activities in ovarian cancer cell lines in vitro. As the most promising candidate of them, compound 20g induced cells apoptosis, arrested the cell cycle at the G1 phase in the A2780 cell line and showed moderate suppression efficacy in a female BALB/C nude mice model. All of the results demonstrated that compound 20g, as the first reported non-ATP competitive small molecule inhibitor of GSK 3β with suppression efficacy on ovarian cancer both in vitro and in vivo, might represent a potential candidate for the treatment of OC.
|
Inhibition of AXL (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
3.4
nM
|
|
Journal : Eur J Med Chem
Title : The discovery of novel benzothiazinones as highly selective non-ATP competitive glycogen synthase kinase 3β inhibitors for the treatment of ovarian cancer.
Year : 2017
Volume : 135
First Page : 370
Last Page : 381
Authors : Gao Y, Ye DY, Zhou WC, Chu Y.
Abstract : Glycogen synthase kinase 3β (GSK 3β) is a highly conserved serine/threonine kinase, and its roles in cancer remain controversial. Cumulative evidence supported that GSK 3β inhibitors could suppress ovarian cancer (OC) development in vitro and made a new direction for ovarian cancer treatment. Here, we reported a series of novel substituted benzothiazinones as non-ATP competitive inhibitors of GSK 3β. Further studies showed that most of them had antiproliferative activities in ovarian cancer cell lines in vitro. As the most promising candidate of them, compound 20g induced cells apoptosis, arrested the cell cycle at the G1 phase in the A2780 cell line and showed moderate suppression efficacy in a female BALB/C nude mice model. All of the results demonstrated that compound 20g, as the first reported non-ATP competitive small molecule inhibitor of GSK 3β with suppression efficacy on ovarian cancer both in vitro and in vivo, might represent a potential candidate for the treatment of OC.
|
Inhibition of VEGFR2 phosphorylation (unknown origin)
|
Homo sapiens
|
0.035
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate.
Year : 2017
Volume : 27
Issue : 15
First Page : 3231
Last Page : 3237
Authors : Li Y, Guo Q, Zhang C, Huang Z, Wang T, Wang X, Wang X, Xu G, Liu Y, Yang S, Fan Y, Xiang R.
Abstract : A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhibition with IC50=12nM. It effectively induced apoptosis in breast and lung cancer cell lines at nanomolar level. Molecular docking of 4d to ATP binding site of CDK9 kinase demonstrated a new hydrogen bonding between F atom of 4-(3-fluorobenzyloxy) group and ASN116 residue, compared with the positive control, LEE011. The compound 4d could block the cell cycle both in G0/G1 and G2/M phase to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with compound 4d showed significant suppression of cancer with low toxicity. Taken together, this novel compound 4d could be a promising drug candidate for clinical application.
|
Inhibition of recombinant human full length c-MET using poly (Glu, Tyr) as substrate by alpha screen assay
|
Homo sapiens
|
1.3
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors.
Year : 2017
Volume : 138
First Page : 942
Last Page : 951
Authors : Zhang L, Zhang B, Zhao J, Zhi Y, Wang L, Lu T, Chen Y.
Abstract : c-Met was emerging as an attractive target for cancer-targeted therapy because deregulation of c-Met has been observed in multiple tumor types. A series of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against MKN45, EBC-1 and PC-3 cell lines. Nine of them showed better activity than lead compound 1 which was found via computer-aided drug design. Among them, compound 8c showed inhibitory activity of 68 nM against c-Met and low micromole cellular potency against MKN45 and EBC-1 cell lines. Moreover, 8c demonstrated more than 50-fold selectivity against other tyrosine kinases tested. The result of western blot indicated that compound 8c was capable of inhibiting the phosphorylation of c-Met kinase in MKN45 cell line in a dose-dependent manner.
|
Inhibition of recombinant human full length VEGFR2 using poly (Glu, Tyr) as substrate by alpha screen assay
|
Homo sapiens
|
0.035
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors.
Year : 2017
Volume : 138
First Page : 942
Last Page : 951
Authors : Zhang L, Zhang B, Zhao J, Zhi Y, Wang L, Lu T, Chen Y.
Abstract : c-Met was emerging as an attractive target for cancer-targeted therapy because deregulation of c-Met has been observed in multiple tumor types. A series of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against MKN45, EBC-1 and PC-3 cell lines. Nine of them showed better activity than lead compound 1 which was found via computer-aided drug design. Among them, compound 8c showed inhibitory activity of 68 nM against c-Met and low micromole cellular potency against MKN45 and EBC-1 cell lines. Moreover, 8c demonstrated more than 50-fold selectivity against other tyrosine kinases tested. The result of western blot indicated that compound 8c was capable of inhibiting the phosphorylation of c-Met kinase in MKN45 cell line in a dose-dependent manner.
|
Inhibition of recombinant human full length KIT using poly (Glu, Tyr) as substrate by alpha screen assay
|
Homo sapiens
|
4.6
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors.
Year : 2017
Volume : 138
First Page : 942
Last Page : 951
Authors : Zhang L, Zhang B, Zhao J, Zhi Y, Wang L, Lu T, Chen Y.
Abstract : c-Met was emerging as an attractive target for cancer-targeted therapy because deregulation of c-Met has been observed in multiple tumor types. A series of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against MKN45, EBC-1 and PC-3 cell lines. Nine of them showed better activity than lead compound 1 which was found via computer-aided drug design. Among them, compound 8c showed inhibitory activity of 68 nM against c-Met and low micromole cellular potency against MKN45 and EBC-1 cell lines. Moreover, 8c demonstrated more than 50-fold selectivity against other tyrosine kinases tested. The result of western blot indicated that compound 8c was capable of inhibiting the phosphorylation of c-Met kinase in MKN45 cell line in a dose-dependent manner.
|
Inhibition of recombinant human full length RET using poly (Glu, Tyr) as substrate by alpha screen assay
|
Homo sapiens
|
5.2
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors.
Year : 2017
Volume : 138
First Page : 942
Last Page : 951
Authors : Zhang L, Zhang B, Zhao J, Zhi Y, Wang L, Lu T, Chen Y.
Abstract : c-Met was emerging as an attractive target for cancer-targeted therapy because deregulation of c-Met has been observed in multiple tumor types. A series of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against MKN45, EBC-1 and PC-3 cell lines. Nine of them showed better activity than lead compound 1 which was found via computer-aided drug design. Among them, compound 8c showed inhibitory activity of 68 nM against c-Met and low micromole cellular potency against MKN45 and EBC-1 cell lines. Moreover, 8c demonstrated more than 50-fold selectivity against other tyrosine kinases tested. The result of western blot indicated that compound 8c was capable of inhibiting the phosphorylation of c-Met kinase in MKN45 cell line in a dose-dependent manner.
|
Inhibition of recombinant human full length AXL using poly (Glu, Tyr) as substrate by alpha screen assay
|
Homo sapiens
|
7.0
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors.
Year : 2017
Volume : 138
First Page : 942
Last Page : 951
Authors : Zhang L, Zhang B, Zhao J, Zhi Y, Wang L, Lu T, Chen Y.
Abstract : c-Met was emerging as an attractive target for cancer-targeted therapy because deregulation of c-Met has been observed in multiple tumor types. A series of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against MKN45, EBC-1 and PC-3 cell lines. Nine of them showed better activity than lead compound 1 which was found via computer-aided drug design. Among them, compound 8c showed inhibitory activity of 68 nM against c-Met and low micromole cellular potency against MKN45 and EBC-1 cell lines. Moreover, 8c demonstrated more than 50-fold selectivity against other tyrosine kinases tested. The result of western blot indicated that compound 8c was capable of inhibiting the phosphorylation of c-Met kinase in MKN45 cell line in a dose-dependent manner.
|
Inhibition of recombinant human full length TIE2 using poly (Glu, Tyr) as substrate by alpha screen assay
|
Homo sapiens
|
14.3
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors.
Year : 2017
Volume : 138
First Page : 942
Last Page : 951
Authors : Zhang L, Zhang B, Zhao J, Zhi Y, Wang L, Lu T, Chen Y.
Abstract : c-Met was emerging as an attractive target for cancer-targeted therapy because deregulation of c-Met has been observed in multiple tumor types. A series of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against MKN45, EBC-1 and PC-3 cell lines. Nine of them showed better activity than lead compound 1 which was found via computer-aided drug design. Among them, compound 8c showed inhibitory activity of 68 nM against c-Met and low micromole cellular potency against MKN45 and EBC-1 cell lines. Moreover, 8c demonstrated more than 50-fold selectivity against other tyrosine kinases tested. The result of western blot indicated that compound 8c was capable of inhibiting the phosphorylation of c-Met kinase in MKN45 cell line in a dose-dependent manner.
|
Inhibition of recombinant human full length FLT3 using poly (Glu, Tyr) as substrate by alpha screen assay
|
Homo sapiens
|
11.3
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors.
Year : 2017
Volume : 138
First Page : 942
Last Page : 951
Authors : Zhang L, Zhang B, Zhao J, Zhi Y, Wang L, Lu T, Chen Y.
Abstract : c-Met was emerging as an attractive target for cancer-targeted therapy because deregulation of c-Met has been observed in multiple tumor types. A series of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against MKN45, EBC-1 and PC-3 cell lines. Nine of them showed better activity than lead compound 1 which was found via computer-aided drug design. Among them, compound 8c showed inhibitory activity of 68 nM against c-Met and low micromole cellular potency against MKN45 and EBC-1 cell lines. Moreover, 8c demonstrated more than 50-fold selectivity against other tyrosine kinases tested. The result of western blot indicated that compound 8c was capable of inhibiting the phosphorylation of c-Met kinase in MKN45 cell line in a dose-dependent manner.
|
Inhibition of c-Met (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
19.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities.
Year : 2018
Volume : 146
First Page : 368
Last Page : 380
Authors : Qi B, Yang Y, He H, Yue X, Zhou Y, Zhou X, Chen Y, Liu M, Zhang A, Wei F.
Abstract : A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging.
|
Inhibition of c-Kit (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
53.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities.
Year : 2018
Volume : 146
First Page : 368
Last Page : 380
Authors : Qi B, Yang Y, He H, Yue X, Zhou Y, Zhou X, Chen Y, Liu M, Zhang A, Wei F.
Abstract : A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging.
|
Inhibition of Ron (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
69.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities.
Year : 2018
Volume : 146
First Page : 368
Last Page : 380
Authors : Qi B, Yang Y, He H, Yue X, Zhou Y, Zhou X, Chen Y, Liu M, Zhang A, Wei F.
Abstract : A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging.
|
Inhibition of KDR (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
0.48
nM
|
|
Journal : Eur J Med Chem
Title : Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities.
Year : 2018
Volume : 146
First Page : 368
Last Page : 380
Authors : Qi B, Yang Y, He H, Yue X, Zhou Y, Zhou X, Chen Y, Liu M, Zhang A, Wei F.
Abstract : A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging.
|
Inhibition of RET (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
37.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities.
Year : 2018
Volume : 146
First Page : 368
Last Page : 380
Authors : Qi B, Yang Y, He H, Yue X, Zhou Y, Zhou X, Chen Y, Liu M, Zhang A, Wei F.
Abstract : A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging.
|
Inhibition of AXL (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
9.5
nM
|
|
Journal : Eur J Med Chem
Title : Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities.
Year : 2018
Volume : 146
First Page : 368
Last Page : 380
Authors : Qi B, Yang Y, He H, Yue X, Zhou Y, Zhou X, Chen Y, Liu M, Zhang A, Wei F.
Abstract : A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging.
|
Inhibition of Src (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
178.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities.
Year : 2018
Volume : 146
First Page : 368
Last Page : 380
Authors : Qi B, Yang Y, He H, Yue X, Zhou Y, Zhou X, Chen Y, Liu M, Zhang A, Wei F.
Abstract : A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging.
|
Antiproliferative activity against mouse BAF3 cells harboring TRP-MET at 1 uM after 72 hrs by CCK-8 assay relative to control
|
Mus musculus
|
97.72
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors.
Year : 2017
Volume : 25
Issue : 24
First Page : 6674
Last Page : 6679
Authors : Li J, Gu W, Bi X, Li H, Liao C, Liu C, Huang W, Qian H.
Abstract : Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
|
Antiproliferative activity against human VEGF-stimulated HUVEC cells at 1 uM after 120 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
72.83
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors.
Year : 2017
Volume : 25
Issue : 24
First Page : 6674
Last Page : 6679
Authors : Li J, Gu W, Bi X, Li H, Liao C, Liu C, Huang W, Qian H.
Abstract : Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
|
Antiproliferative activity against mouse BAF3 cells harboring TRP-MET after 72 hrs by CCK-8 assay
|
Mus musculus
|
24.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors.
Year : 2017
Volume : 25
Issue : 24
First Page : 6674
Last Page : 6679
Authors : Li J, Gu W, Bi X, Li H, Liao C, Liu C, Huang W, Qian H.
Abstract : Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
|
Inhibition of recombinant c-Met (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 60 mins by ELISA
|
Homo sapiens
|
7.2
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors.
Year : 2017
Volume : 25
Issue : 24
First Page : 6674
Last Page : 6679
Authors : Li J, Gu W, Bi X, Li H, Liao C, Liu C, Huang W, Qian H.
Abstract : Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
|
Inhibition of recombinant VEGFR2 (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 60 mins by ELISA
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors.
Year : 2017
Volume : 25
Issue : 24
First Page : 6674
Last Page : 6679
Authors : Li J, Gu W, Bi X, Li H, Liao C, Liu C, Huang W, Qian H.
Abstract : Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
|
Inhibition of TPR-tagged met (unknown origin) expressed in mouse BAF3 cells assessed as inhibition of cell proliferation after 72 hrs by MTT assay
|
Homo sapiens
|
19.86
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Cytotoxicity against HUVEC after 96 hrs by MTT assay
|
Homo sapiens
|
45.0
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Antiproliferative activity against human A549 cells after 72 hrs by MTT assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Antiproliferative activity against human NCI-H292 cells after 72 hrs by MTT assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Antiproliferative activity against human NCI-H460 cells after 72 hrs by MTT assay
|
Homo sapiens
|
40.1
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Antiproliferative activity against human MKN45 cells after 72 hrs by MTT assay
|
Homo sapiens
|
6.9
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Antiproliferative activity against human EBC1 cells after 72 hrs by MTT assay
|
Homo sapiens
|
4.8
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Antiproliferative activity against human SNU5 cells after 72 hrs by MTT assay
|
Homo sapiens
|
12.1
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Inhibition of c-MET (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
3.6
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Inhibition of VEGFR2 (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
3.3
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Inhibition of c-MET (unknown origin)
|
Homo sapiens
|
1.3
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Inhibition of VEGFR2 (unknown origin)
|
Homo sapiens
|
0.035
nM
|
|
Journal : Eur J Med Chem
Title : Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.
Year : 2018
Volume : 158
First Page : 814
Last Page : 831
Authors : Shi W, Qiang H, Huang D, Bi X, Huang W, Qian H.
Abstract : c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
31.71
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of VEGFR2 (unknown origin)
|
Homo sapiens
|
0.035
nM
|
|
Journal : Eur J Med Chem
Title : Evolution in medicinal chemistry of sorafenib derivatives for hepatocellular carcinoma.
Year : 2019
Volume : 179
First Page : 916
Last Page : 935
Authors : Chen F, Fang Y, Zhao R, Le J, Zhang B, Huang R, Chen Z, Shao J.
Abstract : Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Traditional chemotherapy drugs are hard to reach a satisfactory therapeutic effect since advanced HCC is highly chemo-resistant. Sorafenib is an oral multikinase inhibitor that can suppress tumor cell proliferation, angiogenesis and induce cancer cell apoptosis. However, the poor solubility, rapid metabolism and low bioavailability of sorafenib greatly restricted its further clinical application. During the past decade, numerous sorafenib derivatives have been designed and synthesized to overcome its disadvantages and improve its clinical performance. This article focuses on the therapeutic effects and mechanisms of various sorafenib derivatives with modifications on the N-methylpicolinamide group, urea group, central aromatic ring or others. More importantly, this review summarizes the current status of the structure-activity relationship (SAR) of reported sorafenib derivatives, which can provide some detailed information of future directions for further structural modifications of sorafenib to discovery new anti-tumor drugs with improved clinical performance.
|
Inhibition of VEGFR3 (unknown origin)
|
Homo sapiens
|
6.0
nM
|
|
Journal : Eur J Med Chem
Title : Evolution in medicinal chemistry of sorafenib derivatives for hepatocellular carcinoma.
Year : 2019
Volume : 179
First Page : 916
Last Page : 935
Authors : Chen F, Fang Y, Zhao R, Le J, Zhang B, Huang R, Chen Z, Shao J.
Abstract : Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Traditional chemotherapy drugs are hard to reach a satisfactory therapeutic effect since advanced HCC is highly chemo-resistant. Sorafenib is an oral multikinase inhibitor that can suppress tumor cell proliferation, angiogenesis and induce cancer cell apoptosis. However, the poor solubility, rapid metabolism and low bioavailability of sorafenib greatly restricted its further clinical application. During the past decade, numerous sorafenib derivatives have been designed and synthesized to overcome its disadvantages and improve its clinical performance. This article focuses on the therapeutic effects and mechanisms of various sorafenib derivatives with modifications on the N-methylpicolinamide group, urea group, central aromatic ring or others. More importantly, this review summarizes the current status of the structure-activity relationship (SAR) of reported sorafenib derivatives, which can provide some detailed information of future directions for further structural modifications of sorafenib to discovery new anti-tumor drugs with improved clinical performance.
|
Inhibition of c-Met (unknown origin) at 0.05 uM using FAM-labelled peptide and ATP incubated for 10 mins by mobility shift assay relative to control
|
Homo sapiens
|
80.76
%
|
|
Journal : Eur J Med Chem
Title : Discovery of N<sup>1</sup>-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-N<sup>3</sup>-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)urea as a multi-tyrosine kinase inhibitor for drug-sensitive and drug-resistant cancers treatment.
Year : 2019
Volume : 163
First Page : 10
Last Page : 27
Authors : Qi B, Yang Y, Gong G, He H, Yue X, Xu X, Hu Y, Li J, Chen T, Wan X, Zhang A, Zhou G.
Abstract : A series of 21 novel N<sup>1</sup>-(2-aryl-1,3-thiazolidin-4-one)-N<sup>3</sup>-aryl urea derivatives based on the previously identified lead compound I were synthesized and biologically characterized. The most promising compound 19a was identified as a multi-tyrosine kinase inhibitor, including c-Met, Ron, c-Kit, AXL and IGF-1R, etc. The results of real-time live-cell imaging indicated that compound 19a showed improved cytotoxicity and anti-proliferative activity against HT-29 cancer cells in a time- and dose-dependent manner, with an efficacy that was significantly greater than Cabozantinib. Flow cytometry and western blot analysis demonstrated the fact that anticancer activity was closely related with cancer cell apoptosis and the blockade of the phosphorylation of c-Met and its downstream signaling ERK and Akt. Furthermore, compound 19a also displayed slightly stronger effects on HT-29 cancer cells migration than that of Cabozantinib.
|
Inhibition of human recombinant His-tagged cMET expressed in baculovirus expression system reduction in phosphorylation using tyrosine 6 peptide as substrate after 60 mins FRET based Z'-LYTE assay
|
Homo sapiens
|
30.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Structure based designing of triazolopyrimidone-based reversible inhibitors for kinases involved in NSCLC.
Year : 2019
Volume : 29
Issue : 13
First Page : 1565
Last Page : 1571
Authors : Singh PK, Chaudhari D, Jain S, Silakari O.
Abstract : Secondary acquired mutant EGFR (L858R-T790M) overexpressed NSCLC forms one of the prevalent form of resistant NSCLC. Another subset of resistant NSCLC includes amplified cMET in mutant EGFR derived tumours. Thus, in continuation to our previous work on these two major targets of resistant NSCLC, i.e., EGFR (L858R-T790M) and cMET, we are hereby reporting reversible inhibitors of these kinases. Out of 11 lead molecules reported in our previous study, we selected triazolo-pyrimidone (BAS 09867482) scaffold for further development of small molecule dual and reversible inhibitors. Analogues of lead with different substituents on the side ring were sketched and docked in both the target kinases, followed by molecular dynamic simulations. Analogues maintaining hydrophobic interaction with M790 in secondary acquired mutant EGFR (L858R-T790M) were selected and duly synthesized. In vitro biochemical evaluation of these molecules against EGFR (L858R-T790M) and cMET kinase, along with EGFR (L858R) kinase disclosed that three molecules were having significant dual kinase inhibitory potential with IC<sub>50</sub> values well below 100 nM. Further, in vitro anti-proliferative assay against three cell lines (A549, A431 and H460) was performed. Out of all, two compounds were having significant potency against these cell lines.
|
Inhibition of RET V804M mutant (unknown origin)expressed in human BaF3 cells assessed as reduction in cell viability incubated for 48 hrs by celltiter glo luminescence cell viability assay
|
Homo sapiens
|
180.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery and Optimization of wt-RET/KDR-Selective Inhibitors of RETV804M Kinase.
Year : 2020
Volume : 11
Issue : 4
First Page : 497
Last Page : 505
Authors : Newton R, Waszkowycz B, Seewooruthun C, Burschowsky D, Richards M, Hitchin S, Begum H, Watson A, French E, Hamilton N, Jones S, Lin LY, Waddell I, Echalier A, Bayliss R, Jordan AM, Ogilvie D.
Abstract : A combination of focused library and virtual screening, hit expansion, and rational design has resulted in the development of a series of inhibitors of RETV804M kinase, the anticipated drug-resistant mutant of RET kinase. These agents do not inhibit the wild type (wt) isoforms of RET or KDR and therefore offer a potential adjunct to RET inhibitors currently undergoing clinical evaluation.
|
Inhibition of FLT3 (unknown origin) using peptide as substrate preincubated with enzyme for 10 mins followed by substrate addition further incubated for 1 hr by mobility shift assay
|
Homo sapiens
|
418.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis, and biological evaluation of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives as FLT3 inhibitors for the treatment of acute myeloid leukemia.
Year : 2019
Volume : 29
Issue : 19
First Page : 126630
Last Page : 126630
Authors : Xu Q, Dai B, Li Z, Xu L, Yang D, Gong P, Hou Y, Liu Y.
Abstract : FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-N,N'-dimethylacetamide moiety as the linker. The cell proliferation assay in vitro against HL-60 and MV4-11 cell lines demonstrated that most series I compounds containing semicarbazide moiety had more potent than Cabozantinib. Furthermore, the enzyme assay showed that compound 12c and 12g were potent FLT3 inhibitors with IC<sub>50</sub> values of 312 nM and 384 nM, respectively. Following that, molecular docking analysis was also performed to determine possible binding mode between FLT3 and the target compound.
|
Antiproliferative activity against human NIH-H460 cells at 10 uM incubated for 72 hrs by MTT assay relative to control
|
Homo sapiens
|
54.8
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new MET inhibitors with 1,6-naphthyridinone scaffold.
Year : 2020
Volume : 185
First Page : 111803
Last Page : 111803
Authors : Wang MS, Zhuo LS, Yang FP, Wang WJ, Huang W, Yang GF.
Abstract : A potent and novel MET inhibitor, 5-((4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)amino)-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-ones (8), was designed and synthesized via a scaffold-hopping strategy of a 2,7-naphthyridinone MET kinase inhibitor 7. Lead compound 8 had good potency (IC50 of 9.8 nM), but unfavorable pharmacokinetic profiles (F = 12%, CL = 5.0 L/h/kg). Systematic structural optimization of compound 8 resulted in 9g (MET, IC50 = of 9.8 nM) with a comparable MET potency to that of compound 2 and a favorable pharmacokinetic profile (F = 63%, CL = 0.12 L/h/kg). Further study of the derivatization of N(1) amine group of 9g led to the discovery of 23a with good MET potency (IC50 of 7.1 nM), promising VEGFR-2 selectivity (3226-fold), and a markedly drug-likeness improvement (F = 57.7%, CL = 0.02 L/h/kg). The excellent VEGFR-2 selectivity and favorable drug-likeness of 23g suggest that the 1,6-naphthyridine moiety could be used as a new scaffold for kinase inhibitor discovery.
|
Antiproliferative activity against human HT-29 cells at 10 uM incubated for 72 hrs by MTT assay relative to control
|
Homo sapiens
|
29.0
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new MET inhibitors with 1,6-naphthyridinone scaffold.
Year : 2020
Volume : 185
First Page : 111803
Last Page : 111803
Authors : Wang MS, Zhuo LS, Yang FP, Wang WJ, Huang W, Yang GF.
Abstract : A potent and novel MET inhibitor, 5-((4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)amino)-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-ones (8), was designed and synthesized via a scaffold-hopping strategy of a 2,7-naphthyridinone MET kinase inhibitor 7. Lead compound 8 had good potency (IC50 of 9.8 nM), but unfavorable pharmacokinetic profiles (F = 12%, CL = 5.0 L/h/kg). Systematic structural optimization of compound 8 resulted in 9g (MET, IC50 = of 9.8 nM) with a comparable MET potency to that of compound 2 and a favorable pharmacokinetic profile (F = 63%, CL = 0.12 L/h/kg). Further study of the derivatization of N(1) amine group of 9g led to the discovery of 23a with good MET potency (IC50 of 7.1 nM), promising VEGFR-2 selectivity (3226-fold), and a markedly drug-likeness improvement (F = 57.7%, CL = 0.02 L/h/kg). The excellent VEGFR-2 selectivity and favorable drug-likeness of 23g suggest that the 1,6-naphthyridine moiety could be used as a new scaffold for kinase inhibitor discovery.
|
Antiproliferative activity against human MKN45 cells at 10 uM incubated for 72 hrs by MTT assay relative to control
|
Homo sapiens
|
49.1
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new MET inhibitors with 1,6-naphthyridinone scaffold.
Year : 2020
Volume : 185
First Page : 111803
Last Page : 111803
Authors : Wang MS, Zhuo LS, Yang FP, Wang WJ, Huang W, Yang GF.
Abstract : A potent and novel MET inhibitor, 5-((4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)amino)-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-ones (8), was designed and synthesized via a scaffold-hopping strategy of a 2,7-naphthyridinone MET kinase inhibitor 7. Lead compound 8 had good potency (IC50 of 9.8 nM), but unfavorable pharmacokinetic profiles (F = 12%, CL = 5.0 L/h/kg). Systematic structural optimization of compound 8 resulted in 9g (MET, IC50 = of 9.8 nM) with a comparable MET potency to that of compound 2 and a favorable pharmacokinetic profile (F = 63%, CL = 0.12 L/h/kg). Further study of the derivatization of N(1) amine group of 9g led to the discovery of 23a with good MET potency (IC50 of 7.1 nM), promising VEGFR-2 selectivity (3226-fold), and a markedly drug-likeness improvement (F = 57.7%, CL = 0.02 L/h/kg). The excellent VEGFR-2 selectivity and favorable drug-likeness of 23g suggest that the 1,6-naphthyridine moiety could be used as a new scaffold for kinase inhibitor discovery.
|
Inhibition of Aurora A (unknown origin) at 2 uM pre-incubated for 10 mins before FAM-labeled peptide substrate addition by mobility shift assay relative to control
|
Homo sapiens
|
0.4
%
|
|
Journal : Bioorg Med Chem
Title : Optimization and biological evaluation of nicotinamide derivatives as Aurora kinase inhibitors.
Year : 2019
Volume : 27
Issue : 17
First Page : 3825
Last Page : 3835
Authors : Qi B, Xu X, Yang Y, He H, Yue X.
Abstract : Aurora kinases are known to be overexpressed in various solid tumors and implicated in oncogenesis and tumor progression. A series of nicotinamide derivatives were synthesized and their biological activities were evaluated, including kinase inhibitory activity against Aur A and Aur B and in vitro antitumor activity against SW620, HT-29, NCI-H1975 and Hela cancer cell lines. In addition, the study of antiproliferation, cytotoxicity and apoptosis was performed meanwhile. As the most potent inhibitor of Aur A, 4-((3-bromo-4-fluorophenyl)amino)-6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)nicotinamide (10l) showed excellent antitumor activity against SW620 and NCI-H1975 with IC<sub>50</sub> values were 0.61 and 1.06 μM, while the IC<sub>50</sub> values of reference compound were 3.37 and 6.67 μM, respectively. Furthermore, binding mode studies indicated that compound 10l forms better interaction with Aur A.
|
Inhibition of Aurora B (unknown origin) at 2 uM pre-incubated for 10 mins before FAM-labeled peptide substrate addition by mobility shift assay relative to control
|
Homo sapiens
|
38.3
%
|
|
Journal : Bioorg Med Chem
Title : Optimization and biological evaluation of nicotinamide derivatives as Aurora kinase inhibitors.
Year : 2019
Volume : 27
Issue : 17
First Page : 3825
Last Page : 3835
Authors : Qi B, Xu X, Yang Y, He H, Yue X.
Abstract : Aurora kinases are known to be overexpressed in various solid tumors and implicated in oncogenesis and tumor progression. A series of nicotinamide derivatives were synthesized and their biological activities were evaluated, including kinase inhibitory activity against Aur A and Aur B and in vitro antitumor activity against SW620, HT-29, NCI-H1975 and Hela cancer cell lines. In addition, the study of antiproliferation, cytotoxicity and apoptosis was performed meanwhile. As the most potent inhibitor of Aur A, 4-((3-bromo-4-fluorophenyl)amino)-6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)nicotinamide (10l) showed excellent antitumor activity against SW620 and NCI-H1975 with IC<sub>50</sub> values were 0.61 and 1.06 μM, while the IC<sub>50</sub> values of reference compound were 3.37 and 6.67 μM, respectively. Furthermore, binding mode studies indicated that compound 10l forms better interaction with Aur A.
|
Inhibition of c-MET (unknown origin) using FAM-labelled peptide as substrate measured after 10 mins by mobility shift assay
|
Homo sapiens
|
19.0
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of thiazolidin-4-one urea analogues as novel multikinase inhibitors that potently inhibit FLT3 and VEGFR2.
Year : 2019
Volume : 27
Issue : 10
First Page : 2127
Last Page : 2139
Authors : Qi B, Xu X, Yang Y, Zhou Y, Chen T, Gong G, Yue X, Xu X, Hu L, He H.
Abstract : A series of novel thiazolidine-4-one urea analogues were designed, synthesized and biologically evaluated. The structure-activity relationship (SAR) at several positions of the scaffolds was investigated and its binding mode was analyzed by molecular modeling studies. Compound 17b proved to be the most potent one, and IC50 values against A549 and HT-29 cancer cell lines were 0.65 μM and 0.11 μM, respectively. The results of kinase profile demonstrated that compound 17b is a multikinase inhibitor that potently inhibits FLT3 (IC50 = 8.6 nM) and VEGFR2 (IC50 = 18.7 nM). The results of real-time live-cell imaging indicated that compound 17b showed excellent cytotoxicity and anti-proliferative activity against HT-29 cancer cells in a time- and dose-dependent manner, which was significantly potent than that of Cabozantinib. In addition, in vitro antitumor activity was associated with inducing cancer cell apoptosis and suppression of cancer cell migration.
|
Inhibition of recombinant human VEGFR2 (790 to end residues) using myelin ba as substrate at 1 uM incubated for 40 mins by [gamma-33P]-ATP based radiometric assay relative to control
|
Homo sapiens
|
101.0
%
|
|
Journal : Eur J Med Chem
Title : Novel dual inhibitors targeting CDK4 and VEGFR2 synergistically suppressed cancer progression and angiogenesis.
Year : 2019
Volume : 181
First Page : 111541
Last Page : 111541
Authors : Huang Z, Zhao B, Qin Z, Li Y, Wang T, Zhou W, Zheng J, Yang S, Shi Y, Fan Y, Xiang R.
Abstract : Based on the significantly synergistic effects of CDK4 and VEGFR2 inhibitors on growth of cancer cells, a series of novel multi-kinase inhibitors targeting CDK4 and VEGFR2 were designed, synthesized and evaluated, among which Roxyl-ZV-5J exhibited potent and balanced activities against both CDK4 and VEGFR2 with half-maximal inhibitory concentration at the nanomolar level. It effectively induced breast and cervical cancer cell cycle arrest and cell apoptosis. Roxyl-ZV-5J also inhibited the proliferation, tube formation and VEGFR2 downstream signaling pathways of HUVECs. Oral administration of Roxyl-ZV-5J led to significant tumor regression and anti-angiogenesis without obvious toxicity in SiHa xenograft mouse model. In addition, this compound showed good pharmacokinetics. This study confirmed a new tool for dual CDK-VEGFR2 pathways inhibition achieved with a single molecule, which provided valuable leads for further structural optimization and anti-angiogenesis and anti-tumor mechanism study.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
26.38
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
4.79
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.79
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.34
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.01
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
2.85
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.01
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.34
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
2.85
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of c-Met (unknown origin) by caliper mobility shift assay
|
Homo sapiens
|
1.4
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety as potential antitumor inhibitor.
Year : 2020
Volume : 30
Issue : 2
First Page : 126848
Last Page : 126848
Authors : Liu H, Duan Y, Xiong H, Zhang J, Huang S, Chen T, Zheng P, Tang Q.
Abstract : A series of pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety were designed, synthesized and evaluated for the anti-proliferative on three cancer cell lines (A549, HepG2 and MCF-7) in vitro. Most of the compounds showed moderate to high potency. Some excellent compounds were tested for the inhibitory activity of c-Met kinase. Compound 34 (c-Met IC<sub>50</sub> = 17 nM) was investigated the selectivity against Flt-3, c-Kit, VEGFR-2, ALK, PDGFR-β and RON. Structure-activity relationship studies indicated that hydrogen, fluorine atom, and mono-electron-withdrawing groups (mono-EWGs, such as R<sup>2</sup> = F) on R, R<sup>1</sup> and R<sup>2</sup>, respectively, were beneficial for the anti-proliferative activities of the target compounds. Besides, we have took further study on the combined mode between compound 34 and c-Met kinase through molecular docking.
|
Inhibition of human N-terminal GST-fused Axl cytoplasmic domain (464 to 885 residues) expressed in baculovirus expression system at 1 uM using CSKtide as substrate measured after 1 hr by mobility shift assay relative to control
|
Homo sapiens
|
93.0
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of new Axl kinase inhibitors containing 1,3,4-oxadiazole acetamide moiety as novel linker.
Year : 2020
Volume : 186
First Page : 111867
Last Page : 111867
Authors : Xu C,Han Y,Xu S,Wang R,Yue M,Tian Y,Li X,Zhao Y,Gong P
Abstract : Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the primary target. Most of them exhibited moderate to excellent activity, with IC values ranging from 0.032 to 1.54 μM against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase inhibitor (IC = 10 nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and MDA-MB-231 cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the "5- atoms role ".
|
Inhibition of MET (unknown origin) using biotin as substrate preincubated for 5 mins followed by substrate addition and measured after 30 to 60 mins by HTRF assay
|
Homo sapiens
|
8.4
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor drug candidate.
Year : 2020
Volume : 192
First Page : 112174
Last Page : 112174
Authors : Chen T,Zhuo LS,Liu PF,Fang WR,Li YM,Huang W
Abstract : A series of 1,6-naphthyridinone-based MET kinase inhibitors bearing quinoline moiety in block A were designed and synthesized based on the structures of Cabozantinib and our reported compound IV. Extensive SAR and DMPK studies led to the identification of 20j, a potent and orally bioavailable MET kinase inhibitor with favorable kinase selectivity. More importantly, 20j exhibited statistically significant tumor growth inhibition (Tumor growth inhibition/TGI of 131%, 4/6 partial regression/PR) in the U-87 MG xeograft model, which is superior to that of Cabozantinib (TGI of 97%, 2/6 PR), and significantly better than that of compound IV (TGI of 15%, 0/6 PR) at the same dose (12.5 mg/kg). Combined with favorable in vitro potency, kinase selectivity, pharmacokinetic profile and in vivo efficacy, the promising antitumor drug candidate 20j has subsequently advanced into preclinical research.
|
Inhibition of HDAC1 (unknown origin) at 100 nM relative to control
|
Homo sapiens
|
20.9
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel c-Met/HDAC dual inhibitors.
Year : 2020
Volume : 30
Issue : 23
First Page : 127610
Last Page : 127610
Authors : Dong Y,Hu H,Sun Y,Qin M,Gong P,Hou Y,Zhao Y
Abstract : In this work three novel series of c-Met/HDAC bifunctional inhibitors were designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound 11j inhibited c-Met kinase and HDAC1 with IC values of 21.44 and 45.22 nM, respectively. In addition, 11j showed efficient antiproliferative activities against both MCF-7 and A549 cells with greater potency than the reference drug SAHA and Cabozantinib. This work may lay the foundation for developing novel dual c-Met/HDAC inhibitors as potential anticancer therapeutics.
|
Inhibition of c-MET (unknown origin) at 100 nM relative to control
|
Homo sapiens
|
26.3
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel c-Met/HDAC dual inhibitors.
Year : 2020
Volume : 30
Issue : 23
First Page : 127610
Last Page : 127610
Authors : Dong Y,Hu H,Sun Y,Qin M,Gong P,Hou Y,Zhao Y
Abstract : In this work three novel series of c-Met/HDAC bifunctional inhibitors were designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound 11j inhibited c-Met kinase and HDAC1 with IC values of 21.44 and 45.22 nM, respectively. In addition, 11j showed efficient antiproliferative activities against both MCF-7 and A549 cells with greater potency than the reference drug SAHA and Cabozantinib. This work may lay the foundation for developing novel dual c-Met/HDAC inhibitors as potential anticancer therapeutics.
|
Inhibition of c-MET (unknown origin)
|
Homo sapiens
|
37.28
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel c-Met/HDAC dual inhibitors.
Year : 2020
Volume : 30
Issue : 23
First Page : 127610
Last Page : 127610
Authors : Dong Y,Hu H,Sun Y,Qin M,Gong P,Hou Y,Zhao Y
Abstract : In this work three novel series of c-Met/HDAC bifunctional inhibitors were designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound 11j inhibited c-Met kinase and HDAC1 with IC values of 21.44 and 45.22 nM, respectively. In addition, 11j showed efficient antiproliferative activities against both MCF-7 and A549 cells with greater potency than the reference drug SAHA and Cabozantinib. This work may lay the foundation for developing novel dual c-Met/HDAC inhibitors as potential anticancer therapeutics.
|
Inhibition of c-Met (unknown origin) at 1 uM using FAM-labelled peptide and ATP incubated for 10 mins by mobility shift assay relative to control
|
Homo sapiens
|
98.6
%
|
|
Journal : Eur J Med Chem
Title : Identification of novel quinoline analogues bearing thiazolidinones as potent kinase inhibitors for the treatment of colorectal cancer.
Year : 2020
Volume : 204
First Page : 112643
Last Page : 112643
Authors : Zhou Y,Xu X,Wang F,He H,Gong G,Xiong L,Qi B
Abstract : In this investigation, a novel series of quinoline analogues bearing thiazolidinones were designed and synthesized based on our previous study. Among them, the most potent compound 11k, 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ureido)phenoxy)-6-methoxyquinolin-7-yl)oxy)-N-isopropylpiperidine-1-carboxamide, possessed submicromolar c-Met and Ron inhibitory activities. In addition, enzymatic assays against a mini-panel of kinases (c-Kit, B-Raf, c-Src, IGF1R, PDGFRα and AXL) were performed, the results showed that compound 11k exhibited moderate inhibitory activity against PDGFRα, c-Src and AXL. MTT assay revealed in vitro antitumor activities against HT-29 cells of compound 11k with an IC value of 0.31 μM which was 9.3- and 34.2-fold more potent than that of Regorafenib (IC = 2.87 μM) and Cabozantinib (IC = 10.6 μM). Preliminary antitumor mechanisms were also investigated by cellular assays. Considerable cytotoxicity, antiproliferation and induction of apoptosis of compound 11k in a dose- and time-dependent manner were confirmed by IncuCyte live-cell imaging assays. Treatment with compound 11k caused slight G2-or M-phase arrest in HT-29 cells. Further cell selectivity of compound 11k showed that it was not active against human normal colorectal mucosa epithelial cell FHC at 10.0 μg/mL. The above results support further structural modification of compound 11k to improve its inhibitory activity, which will lead to more potent anticancer agents.
|
Inhibition of Ron (unknown origin) at 0.5 uM using FAM-labelled peptide and ATP incubated for 10 mins by mobility shift assay
|
Homo sapiens
|
75.2
%
|
|
Journal : Eur J Med Chem
Title : Identification of novel quinoline analogues bearing thiazolidinones as potent kinase inhibitors for the treatment of colorectal cancer.
Year : 2020
Volume : 204
First Page : 112643
Last Page : 112643
Authors : Zhou Y,Xu X,Wang F,He H,Gong G,Xiong L,Qi B
Abstract : In this investigation, a novel series of quinoline analogues bearing thiazolidinones were designed and synthesized based on our previous study. Among them, the most potent compound 11k, 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ureido)phenoxy)-6-methoxyquinolin-7-yl)oxy)-N-isopropylpiperidine-1-carboxamide, possessed submicromolar c-Met and Ron inhibitory activities. In addition, enzymatic assays against a mini-panel of kinases (c-Kit, B-Raf, c-Src, IGF1R, PDGFRα and AXL) were performed, the results showed that compound 11k exhibited moderate inhibitory activity against PDGFRα, c-Src and AXL. MTT assay revealed in vitro antitumor activities against HT-29 cells of compound 11k with an IC value of 0.31 μM which was 9.3- and 34.2-fold more potent than that of Regorafenib (IC = 2.87 μM) and Cabozantinib (IC = 10.6 μM). Preliminary antitumor mechanisms were also investigated by cellular assays. Considerable cytotoxicity, antiproliferation and induction of apoptosis of compound 11k in a dose- and time-dependent manner were confirmed by IncuCyte live-cell imaging assays. Treatment with compound 11k caused slight G2-or M-phase arrest in HT-29 cells. Further cell selectivity of compound 11k showed that it was not active against human normal colorectal mucosa epithelial cell FHC at 10.0 μg/mL. The above results support further structural modification of compound 11k to improve its inhibitory activity, which will lead to more potent anticancer agents.
|
Inhibition of c-MET(unknown origin) using FAM labelled peptide substrate at 100 nM preincubated for 10 mins followed by substrate addition and measured by microplate reader method
|
Homo sapiens
|
93.1
%
|
|
Journal : Eur J Med Chem
Title : Discovery of Novel c-Mesenchymal-Epithelia transition factor and histone deacetylase dual inhibitors.
Year : 2020
Volume : 204
First Page : 112651
Last Page : 112651
Authors : Hu H,Chen F,Dong Y,Li M,Xu S,Qin M,Gong P
Abstract : Clinically, a single agent that simultaneously inhibits multiple targets has been widely used in cancer treatment to overcome complicated dose design and anti-cancer resistance. Inspired by the synergistic effects between c-Met and HDAC in tumor development, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging the pharmacophores of HDAC inhibitor into a c-Met inhibitor. All the target compounds were evaluated for their biological activity, the most potent compound, 14x, exhibited strong inhibition against HDAC1 with an IC of 18.49 nM and remarkable inhibitory activity against c-Met with an IC of 5.40 nM, respectively. In addition, 14x efficiently inhibited the proliferation of HCT-116, MCF-7 and A549 cell lines with IC values of 0.22 μM, 1.59 μM and 0.22 μM, respectively, which were superior to the reference compounds Cabozantinib and SAHA. Futhermore, 14x induced apoptosis and cause cell cycle arrest in G2/M phase. Docking experiments on c-Met and HDAC enzymes revealed the key interactions between 14x with the target protein. These results indicated that 14x was a potent dual c-Met/HDAC inhibitor and deserved for further investigation.
|
Inhibition of c-MET(unknown origin) using FAM labelled peptide substrate preincubated for 10 mins followed by substrate addition and measured by microplate reader method
|
Homo sapiens
|
37.28
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of Novel c-Mesenchymal-Epithelia transition factor and histone deacetylase dual inhibitors.
Year : 2020
Volume : 204
First Page : 112651
Last Page : 112651
Authors : Hu H,Chen F,Dong Y,Li M,Xu S,Qin M,Gong P
Abstract : Clinically, a single agent that simultaneously inhibits multiple targets has been widely used in cancer treatment to overcome complicated dose design and anti-cancer resistance. Inspired by the synergistic effects between c-Met and HDAC in tumor development, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging the pharmacophores of HDAC inhibitor into a c-Met inhibitor. All the target compounds were evaluated for their biological activity, the most potent compound, 14x, exhibited strong inhibition against HDAC1 with an IC of 18.49 nM and remarkable inhibitory activity against c-Met with an IC of 5.40 nM, respectively. In addition, 14x efficiently inhibited the proliferation of HCT-116, MCF-7 and A549 cell lines with IC values of 0.22 μM, 1.59 μM and 0.22 μM, respectively, which were superior to the reference compounds Cabozantinib and SAHA. Futhermore, 14x induced apoptosis and cause cell cycle arrest in G2/M phase. Docking experiments on c-Met and HDAC enzymes revealed the key interactions between 14x with the target protein. These results indicated that 14x was a potent dual c-Met/HDAC inhibitor and deserved for further investigation.
|
Inhibition of VEGFR2 (unknown origin)
|
Homo sapiens
|
0.035
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Inhibition of RET (unknown origin)
|
Homo sapiens
|
4.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Inhibition of MET (unknown origin)
|
Homo sapiens
|
1.3
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Inhibition of KIT (unknown origin)
|
Homo sapiens
|
4.6
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Inhibition of FLT1 (unknown origin)
|
Homo sapiens
|
12.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Inhibition of FLT2 (unknown origin)
|
Homo sapiens
|
11.3
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Inhibition of FLT3 (unknown origin)
|
Homo sapiens
|
6.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Inhibition of TIE2 (unknown origin)
|
Homo sapiens
|
14.3
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Inhibition of AXL (unknown origin)
|
Homo sapiens
|
7.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Inhibition of c-Met exon 14 deletion mutant (unknown origin) using poly (Glu,Tyr) 4:1 as substrate in presence of ATP by Kinase-Glo Max luminescent assay
|
Homo sapiens
|
29.9
nM
|
|
Journal : ACS Med Chem Lett
Title : trans-Fluorine Effect in Cyclopropane: Diastereoselective Synthesis of Fluorocyclopropyl Cabozantinib Analogs.
Year : 2020
Volume : 11
Issue : 11
First Page : 2146
Last Page : 2150
Authors : Veliks J,Videja M,Kinens A,Bobrovs R,Priede M,Kuka J
Abstract : Investigation of the trans-fluorine effect on the hydrolysis rate of diethyl 2-fluorocyclopropane-1,1-dicarboxylate provides synthetic access to both diastereomers of the fluorocyclopropyl analog of cabozantinib, a c-Met and VEGFR-2 inhibitor used as a first-line treatment for thyroid cancer and as a second-line treatment for renal cell carcinoma. Despite some known potent examples, there are only a few drug molecules that contain fluorocyclopropane moieties. Herein, we present a case study in which the monofluoro analog of a known cyclopropane-containing drug molecule displays an improved in vitro profile compared to the parent nonfluorinated structure. The fluorocyclopropane moiety may offer valuable fine-tuning options for lead optimization in drug discovery.
|
Inhibition of recombinant human RET V804L mutant using KKKVSRSGLYRSP as substrate incubated for 15 mins followed by Mg/ATP addition and measured after 40 mins by [gamma-33P]-ATP assay
|
Homo sapiens
|
76.0
nM
|
|
Journal : Eur J Med Chem
Title : Structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants.
Year : 2018
Volume : 143
First Page : 1148
Last Page : 1164
Authors : Yang J,Chen K,Zhang G,Yang QY,Li YS,Huang SZ,Wang YL,Yang W,Jiang XJ,Yan HX,Zhu JQ,Xiang R,Luo YF,Li WM,Wei YQ,Li LL,Yang SY
Abstract : The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea (17d) is a multi-kinase inhibitor and potently inhibits RET and its drug resistance mutants. It showed IC (half maximal inhibitory concentration) values of 0.010 μM, 0.015 μM, and 0.009 μM against RET-wild-type, RET-V804M, and RET-V804L, respectively. 17d displayed significant anti-viability potencies against various RET-driving tumor cell lines. In a xenograft mouse model of NIH3T3-RET-C634Y, 17d exhibited potent in vivo anti-tumor activity, and no obvious toxicity was observed. Mechanisms of action were also investigated by Western blot and immunohistochemical assays. Collectively, 17d could be a promising agent for the treatment of MTC, hence deserving a further investigation.
|
Inhibition of recombinant human RET V804M mutant using KKKVSRSGLYRSP as substrate incubated for 15 mins followed by Mg/ATP addition and measured after 40 mins by [gamma-33P]-ATP assay
|
Homo sapiens
|
132.0
nM
|
|
Journal : Eur J Med Chem
Title : Structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants.
Year : 2018
Volume : 143
First Page : 1148
Last Page : 1164
Authors : Yang J,Chen K,Zhang G,Yang QY,Li YS,Huang SZ,Wang YL,Yang W,Jiang XJ,Yan HX,Zhu JQ,Xiang R,Luo YF,Li WM,Wei YQ,Li LL,Yang SY
Abstract : The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea (17d) is a multi-kinase inhibitor and potently inhibits RET and its drug resistance mutants. It showed IC (half maximal inhibitory concentration) values of 0.010 μM, 0.015 μM, and 0.009 μM against RET-wild-type, RET-V804M, and RET-V804L, respectively. 17d displayed significant anti-viability potencies against various RET-driving tumor cell lines. In a xenograft mouse model of NIH3T3-RET-C634Y, 17d exhibited potent in vivo anti-tumor activity, and no obvious toxicity was observed. Mechanisms of action were also investigated by Western blot and immunohistochemical assays. Collectively, 17d could be a promising agent for the treatment of MTC, hence deserving a further investigation.
|
Inhibition of recombinant human RET using KKKSPGEYVNIEFG as substrate incubated for 15 mins followed by Mg/ATP addition and measured after 40 mins by [gamma-33P]-ATP assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : Eur J Med Chem
Title : Structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants.
Year : 2018
Volume : 143
First Page : 1148
Last Page : 1164
Authors : Yang J,Chen K,Zhang G,Yang QY,Li YS,Huang SZ,Wang YL,Yang W,Jiang XJ,Yan HX,Zhu JQ,Xiang R,Luo YF,Li WM,Wei YQ,Li LL,Yang SY
Abstract : The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea (17d) is a multi-kinase inhibitor and potently inhibits RET and its drug resistance mutants. It showed IC (half maximal inhibitory concentration) values of 0.010 μM, 0.015 μM, and 0.009 μM against RET-wild-type, RET-V804M, and RET-V804L, respectively. 17d displayed significant anti-viability potencies against various RET-driving tumor cell lines. In a xenograft mouse model of NIH3T3-RET-C634Y, 17d exhibited potent in vivo anti-tumor activity, and no obvious toxicity was observed. Mechanisms of action were also investigated by Western blot and immunohistochemical assays. Collectively, 17d could be a promising agent for the treatment of MTC, hence deserving a further investigation.
|
Inhibition of recombinant MET kinase domain (unknown origin)
|
Homo sapiens
|
8.4
nM
|
|
Journal : Eur J Med Chem
Title : Structure-activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy.
Year : 2020
Volume : 208
First Page : 112785
Last Page : 112785
Authors : Zhuo LS,Wu FX,Wang MS,Xu HC,Yang FP,Tian YG,Zhao XE,Ming ZH,Zhu XL,Hao GF,Huang W
Abstract : As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors. The further pharmacokinetic studies led to the identification of the most promising compound 22a with favorable in vitro potency (MET, IC = 9.0 nM), human microsomal metabolic stability (t = 621.2 min) and oral bioavailability (F = 42%). Moreover, 22a displayed good in vivo antitumor efficacy (IR of 81% in 75 mg/kg) in MET-positive human glioblastoma U-87 MG xenograft model. These positive results indicated that 22a is a potential new MET-targeted antitumor drug lead, which is worthy of further development.
|
Inhibition of MET in human MKN-45 cells assessed as reduction in HGF-mediated autophosphorylation
|
Homo sapiens
|
44.5
nM
|
|
Journal : Eur J Med Chem
Title : Structure-activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy.
Year : 2020
Volume : 208
First Page : 112785
Last Page : 112785
Authors : Zhuo LS,Wu FX,Wang MS,Xu HC,Yang FP,Tian YG,Zhao XE,Ming ZH,Zhu XL,Hao GF,Huang W
Abstract : As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors. The further pharmacokinetic studies led to the identification of the most promising compound 22a with favorable in vitro potency (MET, IC = 9.0 nM), human microsomal metabolic stability (t = 621.2 min) and oral bioavailability (F = 42%). Moreover, 22a displayed good in vivo antitumor efficacy (IR of 81% in 75 mg/kg) in MET-positive human glioblastoma U-87 MG xenograft model. These positive results indicated that 22a is a potential new MET-targeted antitumor drug lead, which is worthy of further development.
|
Inhibition of recombinant VEGFR2 kinase domain (unknown origin)
|
Homo sapiens
|
7.0
nM
|
|
Journal : Eur J Med Chem
Title : Structure-activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy.
Year : 2020
Volume : 208
First Page : 112785
Last Page : 112785
Authors : Zhuo LS,Wu FX,Wang MS,Xu HC,Yang FP,Tian YG,Zhao XE,Ming ZH,Zhu XL,Hao GF,Huang W
Abstract : As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors. The further pharmacokinetic studies led to the identification of the most promising compound 22a with favorable in vitro potency (MET, IC = 9.0 nM), human microsomal metabolic stability (t = 621.2 min) and oral bioavailability (F = 42%). Moreover, 22a displayed good in vivo antitumor efficacy (IR of 81% in 75 mg/kg) in MET-positive human glioblastoma U-87 MG xenograft model. These positive results indicated that 22a is a potential new MET-targeted antitumor drug lead, which is worthy of further development.
|
Cytotoxicity against human A549 cells assessed as inhibition of cell growth measured after 72 hrs by MTT assay
|
Homo sapiens
|
760.0
nM
|
|
|
Cytotoxicity against human HeLa cells assessed as inhibition of cell growth measured after 72 hrs by MTT assay
|
Homo sapiens
|
320.0
nM
|
|
|
Cytotoxicity against human MCF7 cells assessed as inhibition of cell growth measured after 72 hrs by MTT assay
|
Homo sapiens
|
450.0
nM
|
|
|
Inhibition of c-MET kinase (unknown origin) using poly(Glu:Tyr)(4:1) as substrate by ELISA
|
Homo sapiens
|
34.0
nM
|
|
|
Inhibition of wildtype human TRKA using poly (Glu,Tyr) 4:1 as substrate in presence of [gamma-33P]ATP by hotspot kinase assay
|
Homo sapiens
|
72.3
nM
|
|
