SGX-523


CAS No. : 1022150-57-7

SGX-523,1022150-57-7
Product Details
For research use only. Not Intended for Therapeutic Use!
Cat No:I000156
Synonyms:6-[[6-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]quinoline
Molecular Formula:C₁₈H₁₃N₇S
Molecular Weight:359.41
Target:c-MET
IC50:4 nM
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Appearance:Solid powder
Purity: > 98%
Cat No:I000156
Cas No:1022150-57-7
Product-Name:SGX-523
MDL No:MFCD16660190
InChI:1S/C18H13N7S/c1-24-11-13(10-20-24)16-6-7-17-21-22-18(25(17)23-16)26-14-4-5-15-12(9-14)3-2-8-19-15/h2-11H,1H3
InChIKey:BCZUAADEACICHN-UHFFFAOYSA-N
SMILES:CN1C=C(C=N1)C2=NN3C(=NN=C3SC4=CC5=C(C=C4)N=CC=C5)C=C2

SGX523(CAS 1022150-57-7) is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. 

in vitro: SGX-523 belongs to the class of c-Met/hepatocyte growth factor receptor (HGFR) tyrosine kinase inhibitors. SGX-523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for its selectivity. SGX523 potently inhibits the purified MET catalytic domain but not the closely related receptor tyrosine kinase RON. SGX523 indicates ATP-competitive inhibition with higher apparent affinity for the less active, unphosphorylated form of MET [MET-KD(0P), with a Ki of 2.7 nM] versus the more active phospho-enzyme [MET-KD(3P), with a Ki of 23 nM], a phenomenon consistent with preferential binding to an inactive enzyme conformation. SGX523 inhibits MET-mediated signaling, cell proliferation and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations .
in vivo: SGX523 significantly retards the growth of preestablished GTL16 tumors when administered orally at doses of ≥10 mg/kg twice daily. SGX523 potently inhibits U87MG tumor growth; at 30 mg/kg dosed twice daily, SGX523 leads to clear regression of U87MG tumors. SGX523, dosed twice daily at 30 mg/kg, also retards the growth of H441 tumors with concomitant reduction in tumor MET autophosphorylation levels. SGX523 inhibition of MET in vivo is associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma, lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity.

1: Infante JR, Rugg T, Gordon M, Rooney I, Rosen L, Zeh K, Liu R, Burris HA, Ramanathan RK. Unexpected renal toxicity associated with SGX523, a small molecule inhibitor of MET. Invest New Drugs. 2013 Apr;31(2):363-9. doi: 10.1007/s10637-012-9823-9. Epub 2012 May 1. PubMed PMID: 22547164.
2: Zhang YW, Staal B, Essenburg C, Su Y, Kang L, West R, Kaufman D, Dekoning T, Eagleson B, Buchanan SG, Vande Woude GF. MET kinase inhibitor SGX523 synergizes with epidermal growth factor receptor inhibitor erlotinib in a hepatocyte growth factor-dependent fashion to suppress carcinoma growth. Cancer Res. 2010 Sep 1;70(17):6880-90. doi: 10.1158/0008-5472.CAN-10-0898. Epub 2010 Jul 19. Erratum in: Cancer Res. 2011 Apr 1;71(7):2804. PubMed PMID: 20643778.
3: Diamond S, Boer J, Maduskuie TP Jr, Falahatpisheh N, Li Y, Yeleswaram S. Species-specific metabolism of SGX523 by aldehyde oxidase and the toxicological implications. Drug Metab Dispos. 2010 Aug;38(8):1277-85. doi: 10.1124/dmd.110.032375. Epub 2010 Apr 26. PubMed PMID: 20421447.
4: Buchanan SG, Hendle J, Lee PS, Smith CR, Bounaud PY, Jessen KA, Tang CM, Huser NH, Felce JD, Froning KJ, Peterman MC, Aubol BE, Gessert SF, Sauder JM, Schwinn KD, Russell M, Rooney IA, Adams J, Leon BC, Do TH, Blaney JM, Sprengeler PA, Thompson DA, Smyth L, Pelletier LA, Atwell S, Holme K, Wasserman SR, Emtage S, Burley SK, Reich SH. SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. Mol Cancer Ther. 2009 Dec;8(12):3181-90. doi: 10.1158/1535-7163.MCT-09-0477. PubMed PMID: 19934279.
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