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