Therapeutic Targets Database
BIDD Pharmainformatics Databases
 
   
 

 

Target Validation Information
TTD IDTTDC00110
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



 

Welcome to sign our Guestbook.

If you find any error in data or bug in web service, please kindly report it to Dr. Zhu.


Dr. Chen Yuzong
Deputy Director of Center for Computational Science and Engineering
Professor in Department of Pharmacy
National University of Singapore, Singapore


All rights reserved.

 
   
           
 
Computer-aided Drug Design
About BIDD | Databases | Software | Teaching | Research |  Links

Department of Computational Science | National University of Singapore | Blk S17, 3 Science Drive 2, Singapore 117543