PF-04217903 is a triazolopyrazine-based, ATP-competitive inhibitor of c-Met with Ki and cellular IC50 potency of 4 nM and 5 nM, respectively. [1] In a broad panell of over 200 kinases, PF-04217903 showed >1000-fold selectivity for c-Met. For c-Met mutations, PF-04217903 exhibited activities of 6.4 nM, 6.7 nM, and 3.1 nM for endogenous c-Met-R988C, endogenous C-Met-T1010I, and entineered c-Met-H1094R, respectively. [3]

Additionally, PF-04217903 inhibited proliferation, cell survival, migration/invasion in MET-amplified cell lines in vitro and was efficacious in tumor models with either MET gene amplification or hepatocyte growth factor (HGF)/c-Met autocrine loop in vivo. [2, 4] Efficacy was dose-dependent and correlated with inhibition of c-Met phosphorylation and downstream signaling.

Due to its exquisite selectivity profile, PF-04217903 can be considered as a powerful tool in probing c-Met catalytic activity in preclinical models for cancer progression.