Therapeutic Targets Database
BIDD Pharmainformatics Databases


Target Validation Information
Target NameHepatocyte growth factor receptor    
Type of TargetClinical trial target    
Drug Potency against TargetGSK1363089IC50 = 0.4 nM[1]
XL880IC50 = 0.4 nM[1]
SGX523IC50 = 35 nM[1]
ARQ 197IC50 = 50 nM[1]
TAK-701IC50 = 70 nM[2]
XL880Ki = 0.4 nM[3]
3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridineIC50 = 1175 nM[4]
1-benzyl-1H-pyrrolo[3,2-b]pyridineIC50 = 19 nM[4]
BMS-777607IC50 = 20 nM[5]
1-(2-nitrophenethyl)-1H-pyrrolo[3,2-b]pyridineIC50 = 250 nM[4]
1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridineIC50 = 3500 nM[4]
BMS-536924IC50 = 4870 nM[6]
Action against Disease ModelMP470MP470 had an IC50 of 2000 nM in the GIST-R cell line.[7]
The Effect of Target Knockout, Knockdown or Genetic VariationsTo 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 inactivated in 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 uM insulin 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 response to 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.[8]
Ref 1Nat Rev Drug Discov. 2008 Jun;7(6):504-16.Drug development of MET inhibitors: targeting oncogene addiction and expedience. To Reference
Ref 2Curr Top Med Chem. 2005;5(2):215-29.Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. To Reference
Ref 3Cancer Res. 2009 Oct 15;69(20):8009-16. Epub 2009 Oct 6.Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. To Reference
Ref 4Bioorg 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. To Reference
Ref 5J 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. To Reference
Ref 6J 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. To Reference
Ref 7Oncogene. 2007 Jun 7;26(27):3909-19. Epub 2007 Feb 26.A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. To Reference
Ref 8Am J Pathol. 2005 Aug;167(2):429-36.Beta-cell-specific ablation of the hepatocyte growth factor receptor results in reduced islet size, impaired insulin secretion, and glucose intolerance. To Reference


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