Molecule

Description

Cancer

Description

SGX-523 is a selective Met inhibitor with IC50 of 4 nM.

Targets

IC₅₀

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]

Clinical Trials

A phase I clinical trial of SGX523 for the treatment of advanced cancer has been completed.

Features

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 Lines

MDCK cells

Concentrations

200 nM

Incubation Time

18 hours

Methods

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-four hours.

Animal Models

GTL16, U87, or H441 xenografts in Harlan nude mice

Formulation

0.5% MC 400 with 0.05% Tween 80

Doses

60 mg/kg

Administration

Oral gavage