Target Validation Information
Target ID T40474
Target Name Hepatocyte growth factor receptor
Target Type
Successful
Drug Potency against Target BMS-536924 Drug Info IC50 = 4870 nM [527711]
XL880 Drug Info IC50 = 0.4 nM [529502]
SGX523 Drug Info IC50 = 35 nM [529502]
TAK-701 Drug Info IC50 = 70 nM [552513]
3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine Drug Info IC50 = 1175 nM [530081]
1-benzyl-1H-pyrrolo[3,2-b]pyridine Drug Info IC50 = 19 nM [530081]
1-(2-nitrophenethyl)-1H-pyrrolo[3,2-b]pyridine Drug Info IC50 = 250 nM [530081]
Tivantinib Drug Info IC50 = 50 nM [529502]
1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine Drug Info IC50 = 3500 nM [530081]
BMS-777607 Drug Info IC50 = 20 nM [529996]
Action against Disease Model MP470 MP470 had an IC50 of 2000 nM in the GIST-R cell line. [552680] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations To define the role of HGF/c-met signaling in beta-cell biology in vivo, we have generated conditional knockout mice in which the c-met receptor gene was specifically inactivatedin pancreatic beta cells by the Cre-loxP system. Mice with beta-cell-specific deletion of the c-met receptor (betamet-/-) displayed slight growth retardation, mild hyperglycemia, and decreased ser uMinsulin levels at 6 months of age when compared with their control littermates. Deficiency of the c-met receptor in beta cells resulted in a complete loss of acute-phase insulin secretion in responseto glucose and an impaired glucose tolerance. Glucose transporter-2 expression was down-regulated in the beta cells of betamet-/- mice. Compared to controls, betamet-/- mice exhibited reduced islet size and decreased insulin content in the pancreas, but displayed normal islet morphology. Therefore, HGF/c-met signaling plays an imperative role in controlling islet growth, in regulating beta-cell function, and in maintaining glucose homeostasis. [552680]
References
Ref 552680A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 2007 Jun 7;26(27):3909-19. Epub 2007 Feb 26.
Ref 527711J Med Chem. 2005 Sep 8;48(18):5639-43.Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity.
Ref 529502Nat Rev Drug Discov. 2008 Jun;7(6):504-16.Drug development of MET inhibitors: targeting oncogene addiction and expedience.
Ref 529502Nat Rev Drug Discov. 2008 Jun;7(6):504-16.Drug development of MET inhibitors: targeting oncogene addiction and expedience.
Ref 552513Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. Curr Top Med Chem. 2005;5(2):215-29.
Ref 530081Bioorg Med Chem Lett. 2009 May 15;19(10):2780-4. Epub 2009 Mar 27.Discovery of 4-azaindoles as novel inhibitors of c-Met kinase.
Ref 530081Bioorg Med Chem Lett. 2009 May 15;19(10):2780-4. Epub 2009 Mar 27.Discovery of 4-azaindoles as novel inhibitors of c-Met kinase.
Ref 530081Bioorg Med Chem Lett. 2009 May 15;19(10):2780-4. Epub 2009 Mar 27.Discovery of 4-azaindoles as novel inhibitors of c-Met kinase.
Ref 529502Nat Rev Drug Discov. 2008 Jun;7(6):504-16.Drug development of MET inhibitors: targeting oncogene addiction and expedience.
Ref 530081Bioorg Med Chem Lett. 2009 May 15;19(10):2780-4. Epub 2009 Mar 27.Discovery of 4-azaindoles as novel inhibitors of c-Met kinase.
Ref 529996J Med Chem. 2009 Mar 12;52(5):1251-4.Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.

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