SGX-523 - CAS 1022150-57-7
Catalog number: 1022150-57-7
Category: Inhibitor
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SGX523 is a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC50 of 4 nmol/L and is >1,000-fold selective versus the >200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited 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. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition.
Light yellow to yellow solid
SGX-523; SGX 523; SGX523
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SGX Pharmaceuticals.
1.Chemical inhibitors of c-Met receptor tyrosine kinase stimulate osteoblast differentiation and bone regeneration.
Kim JW;Lee MN;Jeong BC;Oh SH;Kook MS;Koh JT Eur J Pharmacol. 2017 Jul 5;806:10-17. doi: 10.1016/j.ejphar.2017.03.032. Epub 2017 Mar 16.
The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been recently introduced to negatively regulate bone morphogenetic protein (BMP)-induced osteogenesis. However, the effect of chemical inhibitors of c-Met receptor on osteoblast differentiation process has not been examined, especially the applicability of c-Met chemical inhibitors on in vivo bone regeneration. In this study, we demonstrated that chemical inhibitors of c-Met receptor tyrosine kinase, SYN1143 and SGX523, could potentiate the differentiation of precursor cells to osteoblasts and stimulate regeneration in calvarial bone defects of mice. Treatment with SYN1143 or SGX523 inhibited HGF-induced c-Met phosphorylation in MC3T3-E1 and C3H10T1/2 cells. Cell proliferation of MC3T3-E1 or C3H10T1/2 was not significantly affected by the concentrations of these inhibitors. Co-treatment with chemical inhibitor of c-Met and osteogenic inducing media enhanced osteoblast-specific genes expression and calcium nodule formation accompanied by increased Runx2 expression via c-Met receptor-dependent but Erk-Smad signaling independent pathway. Notably, the administration of these c-Met inhibitors significantly repaired critical-sized calvarial bone defects.
2.Species-specific metabolism of SGX523 by aldehyde oxidase and the toxicological implications.
Diamond S;Boer J;Maduskuie TP Jr;Falahatpisheh N;Li Y;Yeleswaram S Drug Metab Dispos. 2010 Aug;38(8):1277-85. doi: 10.1124/dmd.110.032375. Epub 2010 Apr 26.
An investigation was conducted to follow up on the apparent species-dependent toxicity reported for 6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoline (SGX523), a mesenchymal-epithelial transition factor (c-MET) inhibitor that entered clinical development for the treatment of solid tumors. Patients treated with SGX523 exhibited compromised renal function presumably resulting from crystal deposits in renal tubules. Our independent metabo'lite profiling of SGX523 indicates that a major NADPH-independent, late-eluting metabolite [6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinolin-2(1H)-one (M11)] was generated by monkey and human liver S-9, and to a lesser extent by rat S-9, whereas M11 was absent in dog S-9 incubations. We confirmed the identity of M11 as 2-quinolinone-SGX523. Experiments with various molybdenum hydroxylase inhibitors showed that aldehyde oxidase (AO), and not xanthine oxidase, metabolized SGX523 to M11 in monkey and human liver cytosol. In addition, the oxygen incorporated into M11 was derived from water rather than atmospheric oxygen, corroborating M11 formation via AO. After oral dosing in monkeys, metabolite profiling of plasma and urine showed that SGX523 was indeed metabolized to M11 and its N-demethyl analog (M8).
3.Strengthening context-dependent anticancer effects on non-small cell lung carcinoma by inhibition of both MET and EGFR.
Zhang YW;Staal B;Essenburg C;Lewis S;Kaufman D;Vande Woude GF Mol Cancer Ther. 2013 Aug;12(8):1429-41. doi: 10.1158/1535-7163.MCT-13-0016. Epub 2013 May 29.
The MET and EGFR receptor tyrosine kinases (RTK) are often coexpressed and may cross-talk in driving the development and progression of non-small cell lung carcinoma (NSCLC). In addition, MET amplification is an alternative resistance mechanism for escaping EGFR-targeted therapy. To assess the benefits of combined targeting of MET and EGFR for treating NSCLCs, we investigated the activities of these two RTK pathways in NSCLC cell lines and evaluated their responses to SGX523 and erlotinib, the small-molecule kinase inhibitors of MET and EGFR, respectively. We showed that MET interacts with and cross-activates EGFR in MET-amplified or -overexpressed cells. The inhibition of both MET and EGFR results in maximal suppression of downstream signaling and of cell proliferation when their ligands are present. Furthermore, we showed that SGX523 plus erlotinib strengthens anticancer activity in vivo in a cellular context-dependent manner. The combination led to the regression of H1993 tumors by enhancing the suppression of proliferation and inducing apoptosis, whereas H1373 tumor growth was significantly reduced by the combination via suppression of proliferation without inducing apoptosis. SGX523 alone was sufficient to achieve near-complete regression of EBC-1 tumors; its combination with erlotinib strongly inhibited the viability of a population of insensitive cells emerging from an SGX523-treated EBC-1 tumor recurrence.
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