SGX-523

 

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Biological Activity

Description	SGX-523 is a selective Met inhibitor with IC50 of 4 nM, no activity to BRAFV599E, c-Raf, Abl and p38α. Phase 1.
Targets	Met
IC50	4 nM [1]
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.[1]
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]
Features

Protocol(Only for Reference)

Kinase Assay: ^[1]

Kinase assays

Initial rate constants are measured at 21 °C in the presence of 100 mM HEPES (pH 7.5), 0.3 mg/mL poly(Glu-Tyr) peptide substrate, 10 mM MgCl2, 1 mg/mL bovine serum albumin, 5% DMSO, 20 nM MET-KD and various concentrations of ATP and SGX523. Total reaction volumes (20 μL) are quenched with 20 μL Kinase-Glo detection buffer. Luminescence is detected in a plate-reading luminometer and the results are analyzed by nonlinear regression.

Cell Assay: ^[1]

Cell lines	MDCK cells
Concentrations	200 nM
Incubation Time	18 hours
Method	MDCK cells are seeded at 1 × 103 per well in a 24-well plate and incubated at 37 °C in 5% CO2 for 1 week in MEM and 10% fetal bovine serum. HGF (90 ng/mL) and various concentrations of SGX523 are added and the cells are incubated for another 18 hours (37 °C, 5% CO2 humidified incubator) and visualized. A549 cells are plated in 12-well plates (6 × 104 per well) and incubated to confluence to investigate cell migration. A channel is introduced into the monolayers by scratching with a pipette tip. Various dilutions of compound are added in starve medium in the presence and absence of HGF (90 ng/mL).The wells are checked for cell migration after twenty-fou

Animal Study: ^[1]

Animal Models	GTL16, U87, or H441 xenografts in Harlan nude mice
Dosages	60 mg/kg
Administration	Oral gavage
Solubility	0.5% methylcellulose/0.2% Tween 80, 30 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT00606879	Terminated	Advanced Cancer	SGX Pharmaceuticals, Inc.	2008-01	Phase 1
NCT00607399	Terminated	Advanced Cancer	SGX Pharmaceuticals, Inc.	2008-01	Phase 1

Chemical Information

Download SGX-523 SDF

Chemical Name	6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoline

Customer Reviews (1)

Click to enlarge	Rating
	Source	Dr. Zhang of Tianjin Medical University. SGX-523 purchased from Selleck
	Method	Western blot
	Cell Lines	Breast cancer cells
	Concentrations	0-1000 nM
	Incubation Time	3 h
	Results	SGX-523 treatment resulted in a reduction of c-Met phosphorylation in Breast cancer cells.

Product Citations (6)

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  The Intrahepatic Signalling Niche of Hedgehog is Defined by Primary Cilia Positive Cells During Chronic Liver Injury. [Grzelak CA, et al. J Hepatol 2013;60(1):143-51]

  
  PubMed: 23978713


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  Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. [Ohashi K, et al. Proc Natl Acad Sci U S A 2012;109(31):E2127-33]

  
  PubMed: 22773810


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  Characteristics of lung cancers harboring NRAS mutations. [Ohashi K, et al. Clin Cancer Res 2013;19(9):2584-91]

  
  PubMed: 23515407