SGX523 is an ATP-competitive, triazolopyridazine-based inhibitor of MET at an IC50 of 4 nM. SGX523 has higher affinity for the unphosphorylated form of MET (Ki = 2.7 nM) than the more active phospho-enzyme (Ki = 23 nM). In a broad panel of 213 kinases, SGX523 was extremely selective, with no inhibition >36%, suggesting IC50 values > 1 uM, including the closely-associated RON kinase. [1]

SGX523 inhibits MET phosphorylation and downstream ERK and AKT activation in a dose-dependent manner, and nearly eliminates HGF-induced MET activation at 1 uM. Downstream inhibition of ERK is enhanced in combination with erlotinib, affectding tyrosine phosphorylation of ErbB3 and EGFR. In HGF-induced NCI-H596 cells, SGX523 exhibited cell cycle inhibition by reducing the number of cells in the S phase from 32% to 9%. [2]

SGX523 was discontinued in Phase I trials due to unexpected toxicity (compromised kidney function, increased serum creatinine).