|
Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr
|
Homo sapiens
|
0.37
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.
Year : 2016
Volume : 59
Issue : 10
First Page : 4948
Last Page : 4964
Authors : Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J, Cai L, Dwight TA, Xu Y, Xu R, Dodd R, Toms A, Parillon L, Lu X, Anjum R, Zhang S, Wang F, Keats J, Wardwell SD, Ning Y, Xu Q, Moran LE, Mohemmad QK, Jang HG, Clackson T, Narasimhan NI, Rivera VM, Zhu X, Dalgarno D, Shakespeare WC.
Abstract : In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
|
Inhibition of human IGF1R using KKKSPGEYVNIEFG as substrate and [gamma-33P]ATP measured after 1 hr
|
Homo sapiens
|
24.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.
Year : 2016
Volume : 59
Issue : 10
First Page : 4948
Last Page : 4964
Authors : Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J, Cai L, Dwight TA, Xu Y, Xu R, Dodd R, Toms A, Parillon L, Lu X, Anjum R, Zhang S, Wang F, Keats J, Wardwell SD, Ning Y, Xu Q, Moran LE, Mohemmad QK, Jang HG, Clackson T, Narasimhan NI, Rivera VM, Zhu X, Dalgarno D, Shakespeare WC.
Abstract : In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
|
Inhibition of human InsR using myelin basic protein as substrate and [gamma-33P]ATP measured after 1 hr
|
Homo sapiens
|
196.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.
Year : 2016
Volume : 59
Issue : 10
First Page : 4948
Last Page : 4964
Authors : Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J, Cai L, Dwight TA, Xu Y, Xu R, Dodd R, Toms A, Parillon L, Lu X, Anjum R, Zhang S, Wang F, Keats J, Wardwell SD, Ning Y, Xu Q, Moran LE, Mohemmad QK, Jang HG, Clackson T, Narasimhan NI, Rivera VM, Zhu X, Dalgarno D, Shakespeare WC.
Abstract : In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
|
Antiproliferative activity against human ALK-positive KARPAS299 cells assessed as reduction in cell viability measured after 72 hrs by CellTiter 96 aqueous one solution cell proliferation assay
|
Homo sapiens
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.
Year : 2016
Volume : 59
Issue : 10
First Page : 4948
Last Page : 4964
Authors : Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J, Cai L, Dwight TA, Xu Y, Xu R, Dodd R, Toms A, Parillon L, Lu X, Anjum R, Zhang S, Wang F, Keats J, Wardwell SD, Ning Y, Xu Q, Moran LE, Mohemmad QK, Jang HG, Clackson T, Narasimhan NI, Rivera VM, Zhu X, Dalgarno D, Shakespeare WC.
Abstract : In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
|
Inhibition of human FLT3 using EAIYAAPFAKKK as substrate and [gamma-33P]ATP measured after 1 hr
|
Homo sapiens
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.
Year : 2016
Volume : 59
Issue : 10
First Page : 4948
Last Page : 4964
Authors : Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J, Cai L, Dwight TA, Xu Y, Xu R, Dodd R, Toms A, Parillon L, Lu X, Anjum R, Zhang S, Wang F, Keats J, Wardwell SD, Ning Y, Xu Q, Moran LE, Mohemmad QK, Jang HG, Clackson T, Narasimhan NI, Rivera VM, Zhu X, Dalgarno D, Shakespeare WC.
Abstract : In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
|
Inhibition of human ROS1 using KKKSPGEYVNIEFG as substrate and [gamma-33P]ATP measured after 1 hr
|
Homo sapiens
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.
Year : 2016
Volume : 59
Issue : 10
First Page : 4948
Last Page : 4964
Authors : Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J, Cai L, Dwight TA, Xu Y, Xu R, Dodd R, Toms A, Parillon L, Lu X, Anjum R, Zhang S, Wang F, Keats J, Wardwell SD, Ning Y, Xu Q, Moran LE, Mohemmad QK, Jang HG, Clackson T, Narasimhan NI, Rivera VM, Zhu X, Dalgarno D, Shakespeare WC.
Abstract : In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
|
Inhibition of recombinant human EGFR T790M/L858R double mutant using poly (Glu,Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
50.9
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of JND3229 as a New EGFRC797S Mutant Inhibitor with In Vivo Monodrug Efficacy.
Year : 2018
Volume : 9
Issue : 11
First Page : 1123
Last Page : 1127
Authors : Lu X, Zhang T, Zhu SJ, Xun Q, Tong L, Hu X, Li Y, Chan S, Su Y, Sun Y, Chen Y, Ding J, Yun CH, Xie H, Ding K.
Abstract : EGFRC797S mutation inducing resistance against third generation EGFR inhibitor drugs is an emerging "unmet clinical need" for nonsmall cell lung cancer patients. The pyrimidopyrimidinone derivative JND3229 was identified as a new highly potent EGFRC797S inhibitor with single digit nM potency. It also exhibited good in vitro and in vivo monodrug anticancer efficacy in a xenograft mouse model of BaF3/EGFR19D/T790M/C797S cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFRT790M/C797S. Our study provides an important structural and chemical basis for future development of new generation EGFRC797S inhibitors as anticancer drugs.
|
Inhibition of recombinant human C-terminal His-tagged/N-terminal GST-tagged EGFR (668 to 1210 residues) T790M/L858R/C797S mutant using poly (Glu,Tyr) 4:1 as substrate after 1 hr by ELISA
|
Homo sapiens
|
38.3
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of JND3229 as a New EGFRC797S Mutant Inhibitor with In Vivo Monodrug Efficacy.
Year : 2018
Volume : 9
Issue : 11
First Page : 1123
Last Page : 1127
Authors : Lu X, Zhang T, Zhu SJ, Xun Q, Tong L, Hu X, Li Y, Chan S, Su Y, Sun Y, Chen Y, Ding J, Yun CH, Xie H, Ding K.
Abstract : EGFRC797S mutation inducing resistance against third generation EGFR inhibitor drugs is an emerging "unmet clinical need" for nonsmall cell lung cancer patients. The pyrimidopyrimidinone derivative JND3229 was identified as a new highly potent EGFRC797S inhibitor with single digit nM potency. It also exhibited good in vitro and in vivo monodrug anticancer efficacy in a xenograft mouse model of BaF3/EGFR19D/T790M/C797S cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFRT790M/C797S. Our study provides an important structural and chemical basis for future development of new generation EGFRC797S inhibitors as anticancer drugs.
|
Antiproliferative activity against mouse BAF3 cells harboring EGFR L858R/T790M/C797S mutant after 72 hrs by resazurin dye based assay
|
Mus musculus
|
420.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of JND3229 as a New EGFRC797S Mutant Inhibitor with In Vivo Monodrug Efficacy.
Year : 2018
Volume : 9
Issue : 11
First Page : 1123
Last Page : 1127
Authors : Lu X, Zhang T, Zhu SJ, Xun Q, Tong L, Hu X, Li Y, Chan S, Su Y, Sun Y, Chen Y, Ding J, Yun CH, Xie H, Ding K.
Abstract : EGFRC797S mutation inducing resistance against third generation EGFR inhibitor drugs is an emerging "unmet clinical need" for nonsmall cell lung cancer patients. The pyrimidopyrimidinone derivative JND3229 was identified as a new highly potent EGFRC797S inhibitor with single digit nM potency. It also exhibited good in vitro and in vivo monodrug anticancer efficacy in a xenograft mouse model of BaF3/EGFR19D/T790M/C797S cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFRT790M/C797S. Our study provides an important structural and chemical basis for future development of new generation EGFRC797S inhibitors as anticancer drugs.
|
Antiproliferative activity against mouse BAF3 cells harboring EGFR 19D/T790M/C797S mutant after 72 hrs by resazurin dye based assay
|
Mus musculus
|
260.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of JND3229 as a New EGFRC797S Mutant Inhibitor with In Vivo Monodrug Efficacy.
Year : 2018
Volume : 9
Issue : 11
First Page : 1123
Last Page : 1127
Authors : Lu X, Zhang T, Zhu SJ, Xun Q, Tong L, Hu X, Li Y, Chan S, Su Y, Sun Y, Chen Y, Ding J, Yun CH, Xie H, Ding K.
Abstract : EGFRC797S mutation inducing resistance against third generation EGFR inhibitor drugs is an emerging "unmet clinical need" for nonsmall cell lung cancer patients. The pyrimidopyrimidinone derivative JND3229 was identified as a new highly potent EGFRC797S inhibitor with single digit nM potency. It also exhibited good in vitro and in vivo monodrug anticancer efficacy in a xenograft mouse model of BaF3/EGFR19D/T790M/C797S cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFRT790M/C797S. Our study provides an important structural and chemical basis for future development of new generation EGFRC797S inhibitors as anticancer drugs.
|
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
|
-0.51
%
|
|
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 wild-type EGFR (unknown origin) using Poly(Glu,Tyr) 4:1 as substrate after 60 mins by ELISA
|
Homo sapiens
|
76.6
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR<sup>L858R/T790M/C797S</sup>).
Year : 2019
Volume : 62
Issue : 15
First Page : 7302
Last Page : 7308
Authors : Shen J, Zhang T, Zhu SJ, Sun M, Tong L, Lai M, Zhang R, Xu W, Wu R, Ding J, Yun CH, Xie H, Lu X, Ding K.
Abstract : Tertiary EGFR<sup>C797S</sup> mutation induced resistance against osimertinib (<b>1</b>) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFR<sup>L858R/T790M/C797S</sup> inhibitors. A representative compound, <b>8r-B</b>, exhibited an IC<sub>50</sub> of 27.5 nM against the EGFR<sup>L858R/T790M/C797S</sup> mutant, while being a significantly less potent for EGFR<sup>WT</sup> (IC<sub>50</sub> > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.
|
Inhibition of human C-terminal His-tagged and N-terminal GST-tagged EGFR L858R/T790M/C797S triple mutant ( 668 to 1210 amino acids) expressed in baculovirus infected Sf9 insect cells using Poly(Glu,Tyr) 4:1 as substrate after 60 mins by ELISA
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR<sup>L858R/T790M/C797S</sup>).
Year : 2019
Volume : 62
Issue : 15
First Page : 7302
Last Page : 7308
Authors : Shen J, Zhang T, Zhu SJ, Sun M, Tong L, Lai M, Zhang R, Xu W, Wu R, Ding J, Yun CH, Xie H, Lu X, Ding K.
Abstract : Tertiary EGFR<sup>C797S</sup> mutation induced resistance against osimertinib (<b>1</b>) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFR<sup>L858R/T790M/C797S</sup> inhibitors. A representative compound, <b>8r-B</b>, exhibited an IC<sub>50</sub> of 27.5 nM against the EGFR<sup>L858R/T790M/C797S</sup> mutant, while being a significantly less potent for EGFR<sup>WT</sup> (IC<sub>50</sub> > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.
|
Antiproliferative activity against mouse BAF3 cells transfected with EGFR L858R/T790M/C797S mutant (unknown origin) incubated for 72 hrs by resazurin dye based assay
|
Mus musculus
|
420.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFR<sup>L858R/T790M/C797S</sup>.
Year : 2019
Volume : 10
Issue : 6
First Page : 869
Last Page : 873
Authors : Li Q, Zhang T, Li S, Tong L, Li J, Su Z, Feng F, Sun D, Tong Y, Wang X, Zhao Z, Zhu L, Ding J, Li H, Xie H, Xu Y.
Abstract : In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFR<sup>L858R/T790M/C797S</sup>. One of the most promising compounds, <b>25g</b>, inhibited the enzymatic activity of EGFR<sup>L858R/T790M/C797S</sup> with an IC<sub>50</sub> value of 2.2 nM. Cell proliferation assays showed that <b>25g</b> effectively and selectively inhibited the growth of EGFR<sup>L858R/T790M/C797S</sup>-dependent cells. This series of compounds, which occupy both the ATP binding site and the allosteric site of the EGFR kinase, may serve as a basis for the development of fourth-generation EGFR inhibitors for L858R/T790M/C797S mutants.
|
Inhibition of C-terminal His-tagged/ N-terminal GST-tagged recombinant human EGFR (668 to 1210 residues) expressed in a Baculovirus infected Sf9 cell expression system using poly-EY as substrate incubated for 30 mins by ADP-Glo kinase assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : J Nat Prod
Title : Discovery of an Oleanolic Acid/Hederagenin-Nitric Oxide Donor Hybrid as an EGFR Tyrosine Kinase Inhibitor for Non-Small-Cell Lung Cancer.
Year : 2019
Volume : 82
Issue : 11
First Page : 3065
Last Page : 3073
Authors : Chen Z, Huang KY, Ling Y, Goto M, Duan HQ, Tong XH, Liu YL, Cheng YY, Morris-Natschke SL, Yang PC, Yang SL, Lee KH.
Abstract : Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 μM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 μM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 μM) than hederagenin (IC50 > 20 μM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 μM) and osimertinib-resistant H1975-LTC (IC50 7.6 μM) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.
|
Inhibition of C-terminal His-tagged/ N-terminal GST-tagged recombinant human EGFR L858R/T790M double mutant (668 to 1210 residues) expressed in a Baculovirus infected Sf9 cell expression system using poly-EY as substrate incubated for 30 mins by ADP-Glo kinase assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : J Nat Prod
Title : Discovery of an Oleanolic Acid/Hederagenin-Nitric Oxide Donor Hybrid as an EGFR Tyrosine Kinase Inhibitor for Non-Small-Cell Lung Cancer.
Year : 2019
Volume : 82
Issue : 11
First Page : 3065
Last Page : 3073
Authors : Chen Z, Huang KY, Ling Y, Goto M, Duan HQ, Tong XH, Liu YL, Cheng YY, Morris-Natschke SL, Yang PC, Yang SL, Lee KH.
Abstract : Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 μM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 μM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 μM) than hederagenin (IC50 > 20 μM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 μM) and osimertinib-resistant H1975-LTC (IC50 7.6 μM) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.
|
Inhibition of C-terminal His-tagged/ N-terminal GST-tagged recombinant human EGFR L858R/T790M/C797S mutant (668 to 1210 residues) expressed in a Baculovirus infected Sf9 cell expression system using poly-EY as substrate incubated for 30 mins by ADP-Glo kinase assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : J Nat Prod
Title : Discovery of an Oleanolic Acid/Hederagenin-Nitric Oxide Donor Hybrid as an EGFR Tyrosine Kinase Inhibitor for Non-Small-Cell Lung Cancer.
Year : 2019
Volume : 82
Issue : 11
First Page : 3065
Last Page : 3073
Authors : Chen Z, Huang KY, Ling Y, Goto M, Duan HQ, Tong XH, Liu YL, Cheng YY, Morris-Natschke SL, Yang PC, Yang SL, Lee KH.
Abstract : Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 μM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 μM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 μM) than hederagenin (IC50 > 20 μM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 μM) and osimertinib-resistant H1975-LTC (IC50 7.6 μM) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.
|
Antiproliferative activity against human NCI-H1975 cells incubated for 72 hrs by MTS assay
|
Homo sapiens
|
620.0
nM
|
|
Journal : J Nat Prod
Title : Discovery of an Oleanolic Acid/Hederagenin-Nitric Oxide Donor Hybrid as an EGFR Tyrosine Kinase Inhibitor for Non-Small-Cell Lung Cancer.
Year : 2019
Volume : 82
Issue : 11
First Page : 3065
Last Page : 3073
Authors : Chen Z, Huang KY, Ling Y, Goto M, Duan HQ, Tong XH, Liu YL, Cheng YY, Morris-Natschke SL, Yang PC, Yang SL, Lee KH.
Abstract : Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 μM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 μM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 μM) than hederagenin (IC50 > 20 μM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 μM) and osimertinib-resistant H1975-LTC (IC50 7.6 μM) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.
|
Antiproliferative activity against human NCI-H1975 cells harbouring EGFR L858R/T790M/C797S mutant incubated for 72 hrs by MTS assay
|
Homo sapiens
|
640.0
nM
|
|
Journal : J Nat Prod
Title : Discovery of an Oleanolic Acid/Hederagenin-Nitric Oxide Donor Hybrid as an EGFR Tyrosine Kinase Inhibitor for Non-Small-Cell Lung Cancer.
Year : 2019
Volume : 82
Issue : 11
First Page : 3065
Last Page : 3073
Authors : Chen Z, Huang KY, Ling Y, Goto M, Duan HQ, Tong XH, Liu YL, Cheng YY, Morris-Natschke SL, Yang PC, Yang SL, Lee KH.
Abstract : Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 μM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 μM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 μM) than hederagenin (IC50 > 20 μM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 μM) and osimertinib-resistant H1975-LTC (IC50 7.6 μM) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
17.19
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
3.746
%
|
|
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
|
-0.22
%
|
|
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
|
-0.04
%
|
|
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
|
-0.04
%
|
|
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
|
-0.22
%
|
|
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 wild type EGFR (unknown origin) by ELISA
|
Homo sapiens
|
48.3
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation.
Year : 2020
Volume : 30
Issue : 16
First Page : 127327
Last Page : 127327
Authors : Su Z, Yang T, Wang J, Lai M, Tong L, Wumaier G, Chen Z, Li S, Li H, Xie H, Zhao Z.
Abstract : The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR<sup>19D/T790M/C797S</sup> mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR<sup>19D/T790M/C797S</sup> (IC<sub>50</sub> = 15.3 nM) and good selectivity over EGFR WT (IC<sub>50</sub> > 1000 nM), L858R/T790M (IC<sub>50</sub>, 156.6 nM) and L858R/T790M/C797S (IC<sub>50</sub>, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR<sup>19D/T790M/C797S</sup> cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR<sup>19D/T790M/C797S</sup> inhibitors.
|
Inhibition of EGFR L858R/T790M mutant (unknown origin) by ELISA
|
Homo sapiens
|
1.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation.
Year : 2020
Volume : 30
Issue : 16
First Page : 127327
Last Page : 127327
Authors : Su Z, Yang T, Wang J, Lai M, Tong L, Wumaier G, Chen Z, Li S, Li H, Xie H, Zhao Z.
Abstract : The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR<sup>19D/T790M/C797S</sup> mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR<sup>19D/T790M/C797S</sup> (IC<sub>50</sub> = 15.3 nM) and good selectivity over EGFR WT (IC<sub>50</sub> > 1000 nM), L858R/T790M (IC<sub>50</sub>, 156.6 nM) and L858R/T790M/C797S (IC<sub>50</sub>, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR<sup>19D/T790M/C797S</sup> cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR<sup>19D/T790M/C797S</sup> inhibitors.
|
Inhibition of EGFR L858R/T790M/C797S mutant (unknown origin) by ELISA
|
Homo sapiens
|
2.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation.
Year : 2020
Volume : 30
Issue : 16
First Page : 127327
Last Page : 127327
Authors : Su Z, Yang T, Wang J, Lai M, Tong L, Wumaier G, Chen Z, Li S, Li H, Xie H, Zhao Z.
Abstract : The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR<sup>19D/T790M/C797S</sup> mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR<sup>19D/T790M/C797S</sup> (IC<sub>50</sub> = 15.3 nM) and good selectivity over EGFR WT (IC<sub>50</sub> > 1000 nM), L858R/T790M (IC<sub>50</sub>, 156.6 nM) and L858R/T790M/C797S (IC<sub>50</sub>, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR<sup>19D/T790M/C797S</sup> cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR<sup>19D/T790M/C797S</sup> inhibitors.
|
Inhibition of EGFR 19D/T790M/C797S mutant (unknown origin) by ELISA
|
Homo sapiens
|
1.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation.
Year : 2020
Volume : 30
Issue : 16
First Page : 127327
Last Page : 127327
Authors : Su Z, Yang T, Wang J, Lai M, Tong L, Wumaier G, Chen Z, Li S, Li H, Xie H, Zhao Z.
Abstract : The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR<sup>19D/T790M/C797S</sup> mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR<sup>19D/T790M/C797S</sup> (IC<sub>50</sub> = 15.3 nM) and good selectivity over EGFR WT (IC<sub>50</sub> > 1000 nM), L858R/T790M (IC<sub>50</sub>, 156.6 nM) and L858R/T790M/C797S (IC<sub>50</sub>, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR<sup>19D/T790M/C797S</sup> cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR<sup>19D/T790M/C797S</sup> inhibitors.
|
Inhibition of EML4/ALK L1196M mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as antiproliferative activity after 72 hrs by CellTiter 96 AQueous One solution
|
Homo sapiens
|
41.0
nM
|
|
Journal : J Med Chem
Title : Medicinal Chemistry Strategies for the Development of Kinase Inhibitors Targeting Point Mutations.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10726
Last Page : 10741
Authors : Lu X,Smaill JB,Ding K
Abstract : Clinically acquired resistance to small molecule kinase inhibitors (SMKIs) has become a major "unmet clinical need" in cancer therapy. To date, there are six SMKIs to be approved for the treatment of cancer patients through targeting of clinically acquired resistance caused by on-target mutations. These are mainly focused on the mutant kinases Bcr-Abl T315I, EGFR T790M, and ALK L1196M. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative SMKIs, such as avoiding steric hindrance, making additional interactions with mutated residues, and forming a covalent bond with an active site cysteine to override resistance observed for reversible inhibitors. Additionally, we also briefly describe allosteric kinase inhibitors and proteolysis targeting chimera (PROTAC) as two other potential strategies while addressing future opportunities in this area.
|
Inhibition of EML4/ALK G1202R mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as antiproliferative activity after 72 hrs by CellTiter 96 AQueous One solution
|
Homo sapiens
|
184.0
nM
|
|
Journal : J Med Chem
Title : Medicinal Chemistry Strategies for the Development of Kinase Inhibitors Targeting Point Mutations.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10726
Last Page : 10741
Authors : Lu X,Smaill JB,Ding K
Abstract : Clinically acquired resistance to small molecule kinase inhibitors (SMKIs) has become a major "unmet clinical need" in cancer therapy. To date, there are six SMKIs to be approved for the treatment of cancer patients through targeting of clinically acquired resistance caused by on-target mutations. These are mainly focused on the mutant kinases Bcr-Abl T315I, EGFR T790M, and ALK L1196M. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative SMKIs, such as avoiding steric hindrance, making additional interactions with mutated residues, and forming a covalent bond with an active site cysteine to override resistance observed for reversible inhibitors. Additionally, we also briefly describe allosteric kinase inhibitors and proteolysis targeting chimera (PROTAC) as two other potential strategies while addressing future opportunities in this area.
|
Inhibition of human ALK G1202R mutant using poly[Glu:Tyr] (4:1) as substrate in presence of [gamma-33P]-ATP assay by radiometric HotSpot assay
|
Homo sapiens
|
4.9
nM
|
|
Journal : J Med Chem
Title : Medicinal Chemistry Strategies for the Development of Kinase Inhibitors Targeting Point Mutations.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10726
Last Page : 10741
Authors : Lu X,Smaill JB,Ding K
Abstract : Clinically acquired resistance to small molecule kinase inhibitors (SMKIs) has become a major "unmet clinical need" in cancer therapy. To date, there are six SMKIs to be approved for the treatment of cancer patients through targeting of clinically acquired resistance caused by on-target mutations. These are mainly focused on the mutant kinases Bcr-Abl T315I, EGFR T790M, and ALK L1196M. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative SMKIs, such as avoiding steric hindrance, making additional interactions with mutated residues, and forming a covalent bond with an active site cysteine to override resistance observed for reversible inhibitors. Additionally, we also briefly describe allosteric kinase inhibitors and proteolysis targeting chimera (PROTAC) as two other potential strategies while addressing future opportunities in this area.
|
Inhibition of human ALK L1196M mutant using poly[Glu:Tyr] (4:1) as substrate in presence of [gamma-33P]-ATP assay by radiometric HotSpot assay
|
Homo sapiens
|
1.7
nM
|
|
Journal : J Med Chem
Title : Medicinal Chemistry Strategies for the Development of Kinase Inhibitors Targeting Point Mutations.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10726
Last Page : 10741
Authors : Lu X,Smaill JB,Ding K
Abstract : Clinically acquired resistance to small molecule kinase inhibitors (SMKIs) has become a major "unmet clinical need" in cancer therapy. To date, there are six SMKIs to be approved for the treatment of cancer patients through targeting of clinically acquired resistance caused by on-target mutations. These are mainly focused on the mutant kinases Bcr-Abl T315I, EGFR T790M, and ALK L1196M. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative SMKIs, such as avoiding steric hindrance, making additional interactions with mutated residues, and forming a covalent bond with an active site cysteine to override resistance observed for reversible inhibitors. Additionally, we also briefly describe allosteric kinase inhibitors and proteolysis targeting chimera (PROTAC) as two other potential strategies while addressing future opportunities in this area.
|
Antiproliferative activity against human SR cells assessed as reduction in cell growth
|
Homo sapiens
|
2.7
nM
|
|
Journal : Eur J Med Chem
Title : Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance.
Year : 2020
Volume : 193
First Page : 112190
Last Page : 112190
Authors : Sun N,Ren C,Kong Y,Zhong H,Chen J,Li Y,Zhang J,Zhou Y,Qiu X,Lin H,Song X,Yang X,Jiang B
Abstract : EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.
|
Antiproliferative activity against human NCI-H2228 cells expressing EML4-ALK assessed as reduction in cell viability incubated for 72 hrs by CCK8 assay
|
Homo sapiens
|
58.2
nM
|
|
Journal : Eur J Med Chem
Title : Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance.
Year : 2020
Volume : 193
First Page : 112190
Last Page : 112190
Authors : Sun N,Ren C,Kong Y,Zhong H,Chen J,Li Y,Zhang J,Zhou Y,Qiu X,Lin H,Song X,Yang X,Jiang B
Abstract : EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.
|
Protac activity at VHL/EML4-ALK G1202R mutant fusion protein (unknown origin) expressed in HEK293T cells assessed as inhibition of cell growth
|
Homo sapiens
|
535.7
nM
|
|
Journal : Eur J Med Chem
Title : Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance.
Year : 2020
Volume : 193
First Page : 112190
Last Page : 112190
Authors : Sun N,Ren C,Kong Y,Zhong H,Chen J,Li Y,Zhang J,Zhou Y,Qiu X,Lin H,Song X,Yang X,Jiang B
Abstract : EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.
|
Antiproliferative activity against human NCI-H1688 cells assessed as inhibition of cell proliferation
|
Homo sapiens
|
691.0
nM
|
|
Journal : Eur J Med Chem
Title : Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance.
Year : 2020
Volume : 193
First Page : 112190
Last Page : 112190
Authors : Sun N,Ren C,Kong Y,Zhong H,Chen J,Li Y,Zhang J,Zhou Y,Qiu X,Lin H,Song X,Yang X,Jiang B
Abstract : EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.
|
Antiproliferative activity against ALK positive human SR cells
|
Homo sapiens
|
1.9
nM
|
|
|
Antiproliferative activity against human NCI-H2228 cells assessed as inhibition of cell proliferation measured by CCK8 assay
|
Homo sapiens
|
31.2
nM
|
|
|
Antiproliferative activity against mouse BaF3 cells overexpressing ALK assessed as inhibition of cell proliferation measured by CCK8 assay
|
Mus musculus
|
8.49
nM
|
|
|
Inhibition of EGFR L858R/T790M/C797S triple mutant (unknown origin) using fluoresceine-labelled poly-GT peptide as substrate incubated for 1 hr by TR-FRET assay
|
Homo sapiens
|
18.5
nM
|
|
|
Inhibition of EGFR L858R/T790M/C797S triple mutant (unknown origin) using fluoresceine-labelled poly-GT peptide as substrate preincubated with enzyme for 3 hrs followed by substrate and ATP addition by TR-FRET assay
|
Homo sapiens
|
12.5
nM
|
|
|
Inhibition of EGFR Ex19del/T790M/C797S triple mutant (unknown origin) incubated for 15 min measured by -CisBio HTRF KinEASE TK
|
Homo sapiens
|
7.0
nM
|
|
|
Inhibition of Wild type EGFR (unknown origin)
|
Homo sapiens
|
21.0
nM
|
|
|
Inhibition of EGFR Ex19del/T790M/C797S triple mutant (unknown origin) expressed in human NCI-H1975 cells assessed as protein phosphorylation measured after 2 hrs by ELISA
|
Homo sapiens
|
459.0
nM
|
|
|
Inhibition of EGFR L858R/T790M mutant (unknown origin) expressed in human NCI-H1975 cells assessed as protein phosphorylation measured after 2 hrs by ELISA
|
Homo sapiens
|
203.0
nM
|
|
|
Inhibition of EGFR Exon19Del/C797S double mutant (unknown origin) by biochemical assay
|
Homo sapiens
|
132.0
nM
|
|
|
Inhibition of EFGR Ex19del (unknown origin) expressed in human PC-9 cells assessed as inhibition of EGF-induced phosphorylation measured after 2 hrs by ELISA
|
Homo sapiens
|
357.0
nM
|
|
|
Antiproliferative activity against human SR cells assessed as inhibition of cell growth incubated for 72 hrs by CCK8 assay
|
Homo sapiens
|
3.3
nM
|
|
|
Antiproliferative activity against human 293T cells overexpressing ALK G1202R mutant assessed as cell growth inhibition after 72 hrs
|
Homo sapiens
|
850.0
nM
|
|
|
Binding affinity to ALK (unknown origin)
|
Homo sapiens
|
1.2
nM
|
|
|
Binding affinity to ALK G1202R mutant (unknown origin)
|
Homo sapiens
|
4.1
nM
|
|
|
Inhibition of cell migration in human MDA-MB-231 cells assessed as wound confluence ratio at 500 nM after 48 hrs by wound healing assay
|
Homo sapiens
|
56.0
%
|
|
|
Inhibition of wild type EGFR (unknown origin) measured by ELISA
|
Homo sapiens
|
261.3
nM
|
|
|
Inhibition of EGFR L858R/T790M double mutant (unknown origin) measured by ELISA
|
Homo sapiens
|
50.9
nM
|
|
|
Inhibition of EGFR L858R/T790M/C797S triple mutant (unknown origin) measured by ELISA
|
Homo sapiens
|
38.3
nM
|
|
|
Antiproliferative activity against mouse BaF3 cells expressing EGFR L858R/T790M/C797S triple mutant assessed as inhibition of cell proliferation measured after 72 hrs by CCK8 assay
|
Mus musculus
|
286.0
nM
|
|
|
Antiproliferative activity against mouse BaF3 cells expressing EGFR 19Del/T790M/C797S triple mutant assessed as inhibition of cell proliferation measured after 72 hrs by CCK8 assay
|
Mus musculus
|
155.0
nM
|
|
|
Antiproliferative activity against human PC-9 cells assessed as inhibition of cell proliferation measured after 72 hrs by CCK8 assay
|
Homo sapiens
|
829.0
nM
|
|
