PF-00337210, a potent, selective and orally bioavailable small molecule inhibitor of VEGFR-2

3992 PF-00337210 is a potent, selective, and orally bioavailable small molecule inhibitor of VEGFRs. It is an ATP-competitive compound that is selective for VEGFR-2 when biochemically profiled against >100 diverse tyrosine and serine-threonine kinases. PF-00337210 preferentially binds to the unactivated kinase (Ki=0.7 nM) relative to the fully phosphorylated form (Ki= 8.8 nM). Crystallographic evidence suggests that its selectivity is likely a result of its ability to bind to a DFG-out conformation of VEGFR-2. In the cell, PF-00337210 inhibits the autophosphorylation of human and murine VEGFR-2 with IC 50 s of 0.87 ± 0.11 nM and 0.83 ± 0.29 nM, respectively. In cell-based assays, the compound is less potent against other split kinase family members: KIT (9.6 ± 3.4 nM), CSF1-R (13 ± 3 nM), PDGFR-α (11 ± 1 nM) and PDGFR-β (29 ± 8 nM), and does not inhibit Flt-3 (IC 50 >10 μM). It also demonstrates greater than 60 fold selectivity for VEGFR-2 versus FGFR-1 in a growth factor stimulated HUVEC survival assay. PF-00337210 shows low to moderate in vivo clearance in several preclinical species (13, 22 and 25 mL/min/kg in rats, dogs and monkeys, respectively). It has high oral bioavailability in rats (>80%) and moderate oral bioavailability in dogs (>30%). In preclinical tumor models, the compound shows dose-dependent anti-tumor efficacy that is associated with significant reduction of microvessel density and vascular permeability in the tumor. The pharmacologically efficacious concentration of PF-00337210 is estimated to be