|
Biochemical Kinase Assay : Recombinant FGFR1 (2.5 nM), or FGFR4 (12 nM) was prepared as a mixture with substrate KKKSPGEYVNIEFG (SEQ ID NO:1) (20 μM, FGFR1 substrate); Poly [E,Y]4:1 (0.2 mg/ml, FGFR2,3,4 substrate)] in kinase reaction buffer (20 mM HEPES-HCl, pH 7.5, 10 mM MgCl2, 2 mM MnCl2, 1 mM EGTA, 0.02% Brij35, 0.1 mM Na3VO4, 0.02 mg/ml BSA, 2 mM DTT, and 1% DMSO). Compound was added to the enzyme/substrate mixture using acoustic technology and pre-incubated for 0, 15, or 60 minutes at room temperature. After compound pre-incubation, 33P-γ-ATP was added at a final concentration of 10 μM to initiate kinase reactions. Reactions were incubated for 120 minutes at room temperature.
|
None
|
13.0
nM
|
|
Title : Pyrimidine FGFR4 inhibitors
Year : 2016
|
Biochemical Kinase Assay : Recombinant FGFR1 (2.5 nM), or FGFR4 (12 nM) was prepared as a mixture with substrate KKKSPGEYVNIEFG (SEQ ID NO:1) (20 μM, FGFR1 substrate); Poly [E,Y]4:1 (0.2 mg/ml, FGFR2,3,4 substrate)] in kinase reaction buffer (20 mM HEPES-HCl, pH 7.5, 10 mM MgCl2, 2 mM MnCl2, 1 mM EGTA, 0.02% Brij35, 0.1 mM Na3VO4, 0.02 mg/ml BSA, 2 mM DTT, and 1% DMSO). Compound was added to the enzyme/substrate mixture using acoustic technology and pre-incubated for 0, 15, or 60 minutes at room temperature. After compound pre-incubation, 33P-γ-ATP was added at a final concentration of 10 μM to initiate kinase reactions. Reactions were incubated for 120 minutes at room temperature.
|
Homo sapiens
|
1.0
nM
|
|
Title : Pyrimidine FGFR4 inhibitors
Year : 2016
|
Inhibition of recombinant FGFR1 (unknown origin) using peptidic substrates in presence of ATP by Kinase-Glo luminescent kinase assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : Eur J Med Chem
Title : An overview of the binding models of FGFR tyrosine kinases in complex with small molecule inhibitors.
Year : 2017
Volume : 126
First Page : 476
Last Page : 490
Authors : Cheng W, Wang M, Tian X, Zhang X.
Abstract : The fibroblast growth factor receptor (FGFR) family receptor tyrosine kinase (RTK) includes four structurally related members, termed as FGFR1, FGFR2, FGFR3, and FGFR4. Given its intimate role in the progression of several solid tumors, excessive FGFR signaling provides an opportunity for anticancer therapy. Along with extensive pharmacological studies validating the therapeutic potential of targeting the FGFRs for cancer treatment, co-crystal structures of FGFRs/inhibitors are continuously coming up to study the mechanism of actions and explore new inhibitors. Herein, we review the reported co-crystals of FGFRs in complex with the corresponding inhibitors, main focusing our attention on the binding models and the pharmacological activities of the inhibitors.
|
Inhibition of recombinant FGFR2 (unknown origin) using peptidic substrates in presence of ATP by Kinase-Glo luminescent kinase assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : Eur J Med Chem
Title : An overview of the binding models of FGFR tyrosine kinases in complex with small molecule inhibitors.
Year : 2017
Volume : 126
First Page : 476
Last Page : 490
Authors : Cheng W, Wang M, Tian X, Zhang X.
Abstract : The fibroblast growth factor receptor (FGFR) family receptor tyrosine kinase (RTK) includes four structurally related members, termed as FGFR1, FGFR2, FGFR3, and FGFR4. Given its intimate role in the progression of several solid tumors, excessive FGFR signaling provides an opportunity for anticancer therapy. Along with extensive pharmacological studies validating the therapeutic potential of targeting the FGFRs for cancer treatment, co-crystal structures of FGFRs/inhibitors are continuously coming up to study the mechanism of actions and explore new inhibitors. Herein, we review the reported co-crystals of FGFRs in complex with the corresponding inhibitors, main focusing our attention on the binding models and the pharmacological activities of the inhibitors.
|
Inhibition of recombinant GST fused FGFR3 (unknown origin) using poly(EY) 4:1 as substrate in presence of [gamma-32P]ATP after 10 mins by scintillation counting method
|
Homo sapiens
|
1.0
nM
|
|
Journal : Eur J Med Chem
Title : An overview of the binding models of FGFR tyrosine kinases in complex with small molecule inhibitors.
Year : 2017
Volume : 126
First Page : 476
Last Page : 490
Authors : Cheng W, Wang M, Tian X, Zhang X.
Abstract : The fibroblast growth factor receptor (FGFR) family receptor tyrosine kinase (RTK) includes four structurally related members, termed as FGFR1, FGFR2, FGFR3, and FGFR4. Given its intimate role in the progression of several solid tumors, excessive FGFR signaling provides an opportunity for anticancer therapy. Along with extensive pharmacological studies validating the therapeutic potential of targeting the FGFRs for cancer treatment, co-crystal structures of FGFRs/inhibitors are continuously coming up to study the mechanism of actions and explore new inhibitors. Herein, we review the reported co-crystals of FGFRs in complex with the corresponding inhibitors, main focusing our attention on the binding models and the pharmacological activities of the inhibitors.
|
Inhibition of recombinant FGFR4 (unknown origin) using peptidic substrates in presence of ATP by Kinase-Glo luminescent kinase assay
|
Homo sapiens
|
60.0
nM
|
|
Journal : Eur J Med Chem
Title : An overview of the binding models of FGFR tyrosine kinases in complex with small molecule inhibitors.
Year : 2017
Volume : 126
First Page : 476
Last Page : 490
Authors : Cheng W, Wang M, Tian X, Zhang X.
Abstract : The fibroblast growth factor receptor (FGFR) family receptor tyrosine kinase (RTK) includes four structurally related members, termed as FGFR1, FGFR2, FGFR3, and FGFR4. Given its intimate role in the progression of several solid tumors, excessive FGFR signaling provides an opportunity for anticancer therapy. Along with extensive pharmacological studies validating the therapeutic potential of targeting the FGFRs for cancer treatment, co-crystal structures of FGFRs/inhibitors are continuously coming up to study the mechanism of actions and explore new inhibitors. Herein, we review the reported co-crystals of FGFRs in complex with the corresponding inhibitors, main focusing our attention on the binding models and the pharmacological activities of the inhibitors.
|
In vivo inhibition of FGFR2 in rat assessed as reduction in bFGF-induced CCL2 production at 10 mg/kg, po measured at 5 hrs post dose relative to control
|
Rattus norvegicus
|
98.2
%
|
|
Journal : J Med Chem
Title : Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors.
Year : 2017
Volume : 60
Issue : 15
First Page : 6516
Last Page : 6527
Authors : Brameld KA, Owens TD, Verner E, Venetsanakos E, Bradshaw JM, Phan VT, Tam D, Leung K, Shu J, LaStant J, Loughhead DG, Ton T, Karr DE, Gerritsen ME, Goldstein DM, Funk JO.
Abstract : Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chemistry optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor.
|
In vivo inhibition of FGFR2 in rat assessed as reduction in bFGF-induced CCL2 production at 10 mg/kg, po measured at 12 hrs post dose relative to control
|
Rattus norvegicus
|
59.5
%
|
|
Journal : J Med Chem
Title : Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors.
Year : 2017
Volume : 60
Issue : 15
First Page : 6516
Last Page : 6527
Authors : Brameld KA, Owens TD, Verner E, Venetsanakos E, Bradshaw JM, Phan VT, Tam D, Leung K, Shu J, LaStant J, Loughhead DG, Ton T, Karr DE, Gerritsen ME, Goldstein DM, Funk JO.
Abstract : Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chemistry optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor.
|
Displacement of [3H]-cyclopamine from SMO V404M mutant in gefitinib resistant human HCC827 cells by scintillation counting
|
Homo sapiens
|
46.5
nM
|
|
Journal : J Med Chem
Title : Dual MET and SMO Negative Modulators Overcome Resistance to EGFR Inhibitors in Human Nonsmall Cell Lung Cancer.
Year : 2017
Volume : 60
Issue : 17
First Page : 7447
Last Page : 7458
Authors : Morgillo F, Amendola G, Della Corte CM, Giacomelli C, Botta L, Di Maro S, Messere A, Ciaramella V, Taliani S, Marinelli L, Trincavelli ML, Martini C, Novellino E, Ciardiello F, Cosconati S.
Abstract : Tyrosine kinase inhibitors (TKIs) of the EGF receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, resistance to these agents frequently occurs, and it is often related to the activation of the Hedgehog (Hh) and MET signaling cascades driving the epithelial-to-mesenchymal transition (EMT). Because the concomitant inhibition of both Hh and MET pathways restores the sensitivity to anti-EGFR drugs, here we aimed at discovering the first compounds that block simultaneously MET and SMO. By using an "in silico drug repurposing" approach and by validating our predictions both in vitro and in vivo, we identified a set of compounds with the desired dual inhibitory activity and enhanced antiproliferative activity on EGFR TKI-resistant NSCLC. The identification of the known MET TKIs, glesatinib and foretinib, as negative modulators of the Hh pathway, widens their application in the context of NSCLC.
|
Inhibition of SMO V404M mutant in gefitinib resistant human HCC827 cells assessed as decrease in GLI1 activity at 2 uM by GLI1 luciferase reporter assay relative to control
|
Homo sapiens
|
25.0
%
|
|
Journal : J Med Chem
Title : Dual MET and SMO Negative Modulators Overcome Resistance to EGFR Inhibitors in Human Nonsmall Cell Lung Cancer.
Year : 2017
Volume : 60
Issue : 17
First Page : 7447
Last Page : 7458
Authors : Morgillo F, Amendola G, Della Corte CM, Giacomelli C, Botta L, Di Maro S, Messere A, Ciaramella V, Taliani S, Marinelli L, Trincavelli ML, Martini C, Novellino E, Ciardiello F, Cosconati S.
Abstract : Tyrosine kinase inhibitors (TKIs) of the EGF receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, resistance to these agents frequently occurs, and it is often related to the activation of the Hedgehog (Hh) and MET signaling cascades driving the epithelial-to-mesenchymal transition (EMT). Because the concomitant inhibition of both Hh and MET pathways restores the sensitivity to anti-EGFR drugs, here we aimed at discovering the first compounds that block simultaneously MET and SMO. By using an "in silico drug repurposing" approach and by validating our predictions both in vitro and in vivo, we identified a set of compounds with the desired dual inhibitory activity and enhanced antiproliferative activity on EGFR TKI-resistant NSCLC. The identification of the known MET TKIs, glesatinib and foretinib, as negative modulators of the Hh pathway, widens their application in the context of NSCLC.
|
Inhibition of SMO V404M mutant in gefitinib resistant human HCC827 cells assessed as decrease in GLI1 activity at 60 uM by GLI1 luciferase reporter assay relative to control
|
Homo sapiens
|
10.0
%
|
|
Journal : J Med Chem
Title : Dual MET and SMO Negative Modulators Overcome Resistance to EGFR Inhibitors in Human Nonsmall Cell Lung Cancer.
Year : 2017
Volume : 60
Issue : 17
First Page : 7447
Last Page : 7458
Authors : Morgillo F, Amendola G, Della Corte CM, Giacomelli C, Botta L, Di Maro S, Messere A, Ciaramella V, Taliani S, Marinelli L, Trincavelli ML, Martini C, Novellino E, Ciardiello F, Cosconati S.
Abstract : Tyrosine kinase inhibitors (TKIs) of the EGF receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, resistance to these agents frequently occurs, and it is often related to the activation of the Hedgehog (Hh) and MET signaling cascades driving the epithelial-to-mesenchymal transition (EMT). Because the concomitant inhibition of both Hh and MET pathways restores the sensitivity to anti-EGFR drugs, here we aimed at discovering the first compounds that block simultaneously MET and SMO. By using an "in silico drug repurposing" approach and by validating our predictions both in vitro and in vivo, we identified a set of compounds with the desired dual inhibitory activity and enhanced antiproliferative activity on EGFR TKI-resistant NSCLC. The identification of the known MET TKIs, glesatinib and foretinib, as negative modulators of the Hh pathway, widens their application in the context of NSCLC.
|
Inhibition of phosphorylated FGFR4 (388 to 802 residues) (unknown origin) using 5-Fluo-Ahx-KKKKEEIYFFFG-NH2 as substrate after 60 mins by microfluidic mobility shift assay
|
Homo sapiens
|
71.0
nM
|
|
Journal : MedChemComm
Title : Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region.
Year : 2017
Volume : 8
Issue : 8
First Page : 1604
Last Page : 1613
Authors : Fairhurst RA, Knoepfel T, Leblanc C, Buschmann N, Gaul C, Blank J, Galuba I, Trappe J, Zou C, Voshol J, Genick C, Brunet-Lefeuvre P, Bitsch F, Graus-Porta D, Furet P.
Abstract : A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.
|
Inhibition of phosphorylated FGFR1 (407 to 822 residues) (unknown origin) using 5-Fluo-Ahx-EEPLYWSFPAKKKCONH2 as substrate after 60 mins by microfluidic mobility shift assay
|
Homo sapiens
|
0.8
nM
|
|
Journal : MedChemComm
Title : Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region.
Year : 2017
Volume : 8
Issue : 8
First Page : 1604
Last Page : 1613
Authors : Fairhurst RA, Knoepfel T, Leblanc C, Buschmann N, Gaul C, Blank J, Galuba I, Trappe J, Zou C, Voshol J, Genick C, Brunet-Lefeuvre P, Bitsch F, Graus-Porta D, Furet P.
Abstract : A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.
|
Inhibition of phosphorylated FGFR2 (406 to 821 residues) (unknown origin) using 5-Fluo-Ahx-EEPLYWSFPAKKKCONH2 as substrate after 60 mins by microfluidic mobility shift assay
|
Homo sapiens
|
1.2
nM
|
|
Journal : MedChemComm
Title : Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region.
Year : 2017
Volume : 8
Issue : 8
First Page : 1604
Last Page : 1613
Authors : Fairhurst RA, Knoepfel T, Leblanc C, Buschmann N, Gaul C, Blank J, Galuba I, Trappe J, Zou C, Voshol J, Genick C, Brunet-Lefeuvre P, Bitsch F, Graus-Porta D, Furet P.
Abstract : A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.
|
Inhibition of phosphorylated FGFR3 (411 to 806 residues) (unknown origin) using 5-Fluo-Ahx-EEPLYWSFPAKKKCONH2 as substrate after 60 mins by microfluidic mobility shift assay
|
Homo sapiens
|
1.8
nM
|
|
Journal : MedChemComm
Title : Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region.
Year : 2017
Volume : 8
Issue : 8
First Page : 1604
Last Page : 1613
Authors : Fairhurst RA, Knoepfel T, Leblanc C, Buschmann N, Gaul C, Blank J, Galuba I, Trappe J, Zou C, Voshol J, Genick C, Brunet-Lefeuvre P, Bitsch F, Graus-Porta D, Furet P.
Abstract : A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.
|
Inhibition of wild type non-phosphorylated N-terminal His6-tagged FGFR4 (G442 to E753 residues) (unknown origin) expressed in sf9 cells using 5-Fluo-Ahx-KKKKEEIYFFFG-NH2 as substrate after 60 mins by microfluidic mobility shift assay
|
Homo sapiens
|
62.0
nM
|
|
Journal : MedChemComm
Title : Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region.
Year : 2017
Volume : 8
Issue : 8
First Page : 1604
Last Page : 1613
Authors : Fairhurst RA, Knoepfel T, Leblanc C, Buschmann N, Gaul C, Blank J, Galuba I, Trappe J, Zou C, Voshol J, Genick C, Brunet-Lefeuvre P, Bitsch F, Graus-Porta D, Furet P.
Abstract : A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.
|
Inhibition of non-phosphorylated N-terminal His6-tagged FGFR4 C552A mutant (G442 to E753 residues) (unknown origin) expressed in sf9 cells using 5-Fluo-Ahx-KKKKEEIYFFFG-NH2 as substrate after 60 mins by microfluidic mobility shift assay
|
Homo sapiens
|
0.82
nM
|
|
Journal : MedChemComm
Title : Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region.
Year : 2017
Volume : 8
Issue : 8
First Page : 1604
Last Page : 1613
Authors : Fairhurst RA, Knoepfel T, Leblanc C, Buschmann N, Gaul C, Blank J, Galuba I, Trappe J, Zou C, Voshol J, Genick C, Brunet-Lefeuvre P, Bitsch F, Graus-Porta D, Furet P.
Abstract : A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.
|
Inhibition of non-phosphorylated N-terminal His6-tagged FGFR4 C477A mutant (G442 to E753 residues) (unknown origin) expressed in sf9 cells using 5-Fluo-Ahx-KKKKEEIYFFFG-NH2 as substrate after 60 mins by microfluidic mobility shift assay
|
Homo sapiens
|
64.0
nM
|
|
Journal : MedChemComm
Title : Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region.
Year : 2017
Volume : 8
Issue : 8
First Page : 1604
Last Page : 1613
Authors : Fairhurst RA, Knoepfel T, Leblanc C, Buschmann N, Gaul C, Blank J, Galuba I, Trappe J, Zou C, Voshol J, Genick C, Brunet-Lefeuvre P, Bitsch F, Graus-Porta D, Furet P.
Abstract : A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.
|
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
|
-0.85
%
|
|
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.
|
Antiproliferative activity against FGFR3 amplified human RT112 cells after 72 hrs by CCK8 or MTT assay
|
Homo sapiens
|
0.5
nM
|
|
Journal : J Med Chem
Title : Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors.
Year : 2018
Volume : 61
Issue : 20
First Page : 9085
Last Page : 9104
Authors : Wang Y, Li L, Fan J, Dai Y, Jiang A, Geng M, Ai J, Duan W.
Abstract : Fibroblast growth factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2). In in vivo studies, 9g displayed clear antitumor activities in NCI-H1581 and SNU-16 xenograft mice models. Additionally, the diluting method confirmed the irreversible binding of 9g to FGFR.
|
Antiproliferative activity against FGF19/FGFR4 expressing human HuH7 cells after 72 hrs by CCK8 or MTT assay
|
Homo sapiens
|
57.2
nM
|
|
Journal : J Med Chem
Title : Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors.
Year : 2018
Volume : 61
Issue : 20
First Page : 9085
Last Page : 9104
Authors : Wang Y, Li L, Fan J, Dai Y, Jiang A, Geng M, Ai J, Duan W.
Abstract : Fibroblast growth factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2). In in vivo studies, 9g displayed clear antitumor activities in NCI-H1581 and SNU-16 xenograft mice models. Additionally, the diluting method confirmed the irreversible binding of 9g to FGFR.
|
Antiproliferative activity against mouse BAF3 cells expressing TEL-fused FGFR4 kinase after 72 hrs by CCK8 or MTT assay
|
Mus musculus
|
132.6
nM
|
|
Journal : J Med Chem
Title : Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors.
Year : 2018
Volume : 61
Issue : 20
First Page : 9085
Last Page : 9104
Authors : Wang Y, Li L, Fan J, Dai Y, Jiang A, Geng M, Ai J, Duan W.
Abstract : Fibroblast growth factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2). In in vivo studies, 9g displayed clear antitumor activities in NCI-H1581 and SNU-16 xenograft mice models. Additionally, the diluting method confirmed the irreversible binding of 9g to FGFR.
|
Inhibition of N-terminal GST-tagged human FGFR1 cytoplasmic domain (398-822 AA) expressed in baculovirus using FAM-labelled peptide as substrate pre-incubated for 10 mins followed by substrate addition by mobility shift assay
|
Homo sapiens
|
0.59
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of 4,6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC.
Year : 2020
Volume : 187
First Page : 111943
Last Page : 111943
Authors : Xie Z, Wu K, Wang Y, Pan Y, Chen B, Cheng D, Pan S, Guo T, Du X, Fang L, Wang X, Ye F.
Abstract : FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity <sup>1</sup>and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC<sub>50</sub> values for H226 and HCC827 GR were 2.11 μM, and 0.93 μM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.
|
Antiproliferative activity against human HCC827 cells assessed as inhibition of cell growth at 10 uM incubated for 48 hrs by MTT assay relative to control
|
Homo sapiens
|
32.05
%
|
|
Journal : Eur J Med Chem
Title : Discovery of 4,6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC.
Year : 2020
Volume : 187
First Page : 111943
Last Page : 111943
Authors : Xie Z, Wu K, Wang Y, Pan Y, Chen B, Cheng D, Pan S, Guo T, Du X, Fang L, Wang X, Ye F.
Abstract : FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity <sup>1</sup>and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC<sub>50</sub> values for H226 and HCC827 GR were 2.11 μM, and 0.93 μM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.
|
Antiproliferative activity against human PC9 cells assessed as inhibition of cell growth at 10 uM incubated for 48 hrs by MTT assay relative to control
|
Homo sapiens
|
55.5
%
|
|
Journal : Eur J Med Chem
Title : Discovery of 4,6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC.
Year : 2020
Volume : 187
First Page : 111943
Last Page : 111943
Authors : Xie Z, Wu K, Wang Y, Pan Y, Chen B, Cheng D, Pan S, Guo T, Du X, Fang L, Wang X, Ye F.
Abstract : FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity <sup>1</sup>and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC<sub>50</sub> values for H226 and HCC827 GR were 2.11 μM, and 0.93 μM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.
|
Antiproliferative activity against human NCI-H520 cells assessed as inhibition of cell growth at 10 uM incubated for 48 hrs by MTT assay relative to control
|
Homo sapiens
|
77.09
%
|
|
Journal : Eur J Med Chem
Title : Discovery of 4,6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC.
Year : 2020
Volume : 187
First Page : 111943
Last Page : 111943
Authors : Xie Z, Wu K, Wang Y, Pan Y, Chen B, Cheng D, Pan S, Guo T, Du X, Fang L, Wang X, Ye F.
Abstract : FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity <sup>1</sup>and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC<sub>50</sub> values for H226 and HCC827 GR were 2.11 μM, and 0.93 μM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.
|
Antiproliferative activity against human NCI-H1581 cells assessed as inhibition of cell growth at 10 uM incubated for 48 hrs by MTT assay relative to control
|
Homo sapiens
|
83.67
%
|
|
Journal : Eur J Med Chem
Title : Discovery of 4,6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC.
Year : 2020
Volume : 187
First Page : 111943
Last Page : 111943
Authors : Xie Z, Wu K, Wang Y, Pan Y, Chen B, Cheng D, Pan S, Guo T, Du X, Fang L, Wang X, Ye F.
Abstract : FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity <sup>1</sup>and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC<sub>50</sub> values for H226 and HCC827 GR were 2.11 μM, and 0.93 μM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.
|
Antiproliferative activity against human NCI-H226 cells assessed as inhibition of cell growth at 10 uM incubated for 48 hrs by MTT assay relative to control
|
Homo sapiens
|
67.33
%
|
|
Journal : Eur J Med Chem
Title : Discovery of 4,6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC.
Year : 2020
Volume : 187
First Page : 111943
Last Page : 111943
Authors : Xie Z, Wu K, Wang Y, Pan Y, Chen B, Cheng D, Pan S, Guo T, Du X, Fang L, Wang X, Ye F.
Abstract : FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity <sup>1</sup>and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC<sub>50</sub> values for H226 and HCC827 GR were 2.11 μM, and 0.93 μM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
16.52
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
11.01
%
|
|
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
|
0.24
%
|
|
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
|
0.1
%
|
|
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
|
0.24
%
|
|
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
|
0.1
%
|
|
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.
|
Antiproliferative activity against human HuH7 cells assessed as reduction in cell viability incubated for 3 days by cell proliferation assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12542
Last Page : 12573
Authors : Fairhurst RA,Knoepfel T,Buschmann N,Leblanc C,Mah R,Todorov M,Nimsgern P,Ripoche S,Niklaus M,Warin N,Luu VH,Madoerin M,Wirth J,Graus-Porta D,Weiss A,Kiffe M,Wartmann M,Kinyamu-Akunda J,Sterker D,Stamm C,Adler F,Buhles A,Schadt H,Couttet P,Blank J,Galuba I,Trappe J,Voshol J,Ostermann N,Zou C,Berghausen J,Del Rio Espinola A,Jahnke W,Furet P
Abstract : FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.
|
Inhibition of FGFR4 in mouse BAF3 cells assessed as reduction in cell viability incubated for 2 days by cell proliferation assay
|
Mus musculus
|
581.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12542
Last Page : 12573
Authors : Fairhurst RA,Knoepfel T,Buschmann N,Leblanc C,Mah R,Todorov M,Nimsgern P,Ripoche S,Niklaus M,Warin N,Luu VH,Madoerin M,Wirth J,Graus-Porta D,Weiss A,Kiffe M,Wartmann M,Kinyamu-Akunda J,Sterker D,Stamm C,Adler F,Buhles A,Schadt H,Couttet P,Blank J,Galuba I,Trappe J,Voshol J,Ostermann N,Zou C,Berghausen J,Del Rio Espinola A,Jahnke W,Furet P
Abstract : FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.
|
Inhibition of FGFR4 in mouse BAF3 cells assessed as decrease in FGFR4 phosphorylation incubated for 40 mins
|
Mus musculus
|
541.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12542
Last Page : 12573
Authors : Fairhurst RA,Knoepfel T,Buschmann N,Leblanc C,Mah R,Todorov M,Nimsgern P,Ripoche S,Niklaus M,Warin N,Luu VH,Madoerin M,Wirth J,Graus-Porta D,Weiss A,Kiffe M,Wartmann M,Kinyamu-Akunda J,Sterker D,Stamm C,Adler F,Buhles A,Schadt H,Couttet P,Blank J,Galuba I,Trappe J,Voshol J,Ostermann N,Zou C,Berghausen J,Del Rio Espinola A,Jahnke W,Furet P
Abstract : FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.
|
Inhibition of recombinant non-phosphorylated FGFR4 kinase domain (442 to 753) (unknown origin) expressed in Sf9 insect cells using 5-Fluo-Ahx-KKKKEEIYFFFG-NH2 peptide as substrate in presence of ATP measured after 60 mins by caliper microfluidic mobility shift assay
|
Homo sapiens
|
71.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12542
Last Page : 12573
Authors : Fairhurst RA,Knoepfel T,Buschmann N,Leblanc C,Mah R,Todorov M,Nimsgern P,Ripoche S,Niklaus M,Warin N,Luu VH,Madoerin M,Wirth J,Graus-Porta D,Weiss A,Kiffe M,Wartmann M,Kinyamu-Akunda J,Sterker D,Stamm C,Adler F,Buhles A,Schadt H,Couttet P,Blank J,Galuba I,Trappe J,Voshol J,Ostermann N,Zou C,Berghausen J,Del Rio Espinola A,Jahnke W,Furet P
Abstract : FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.
|
Antiproliferative activity against human Hep3B cells assessed as reduction in cell viability by cell proliferation assay
|
Homo sapiens
|
85.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12542
Last Page : 12573
Authors : Fairhurst RA,Knoepfel T,Buschmann N,Leblanc C,Mah R,Todorov M,Nimsgern P,Ripoche S,Niklaus M,Warin N,Luu VH,Madoerin M,Wirth J,Graus-Porta D,Weiss A,Kiffe M,Wartmann M,Kinyamu-Akunda J,Sterker D,Stamm C,Adler F,Buhles A,Schadt H,Couttet P,Blank J,Galuba I,Trappe J,Voshol J,Ostermann N,Zou C,Berghausen J,Del Rio Espinola A,Jahnke W,Furet P
Abstract : FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.
|
Antiproliferative activity against human Rh41 cells assessed as reduction in cell viability measured after 3 days
|
Homo sapiens
|
172.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12542
Last Page : 12573
Authors : Fairhurst RA,Knoepfel T,Buschmann N,Leblanc C,Mah R,Todorov M,Nimsgern P,Ripoche S,Niklaus M,Warin N,Luu VH,Madoerin M,Wirth J,Graus-Porta D,Weiss A,Kiffe M,Wartmann M,Kinyamu-Akunda J,Sterker D,Stamm C,Adler F,Buhles A,Schadt H,Couttet P,Blank J,Galuba I,Trappe J,Voshol J,Ostermann N,Zou C,Berghausen J,Del Rio Espinola A,Jahnke W,Furet P
Abstract : FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.
|
Antiproliferative activity against human JHH7 cells assessed as reduction in cell viability by cell proliferation assay
|
Homo sapiens
|
67.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12542
Last Page : 12573
Authors : Fairhurst RA,Knoepfel T,Buschmann N,Leblanc C,Mah R,Todorov M,Nimsgern P,Ripoche S,Niklaus M,Warin N,Luu VH,Madoerin M,Wirth J,Graus-Porta D,Weiss A,Kiffe M,Wartmann M,Kinyamu-Akunda J,Sterker D,Stamm C,Adler F,Buhles A,Schadt H,Couttet P,Blank J,Galuba I,Trappe J,Voshol J,Ostermann N,Zou C,Berghausen J,Del Rio Espinola A,Jahnke W,Furet P
Abstract : FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.
|
Inhibition of FGFR1 (unknown origin)
|
Homo sapiens
|
0.9
nM
|
|
|
Inhibition of FGFR2 (unknown origin)
|
Homo sapiens
|
1.4
nM
|
|
|
Inhibition of FGFR3 (unknown origin)
|
Homo sapiens
|
1.0
nM
|
|
|
Inhibition of FGFR4 (unknown origin)
|
Homo sapiens
|
60.0
nM
|
|
