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

作者：Tami Marrone, Dana D. Hu‐Lowe, Maren L. Grazzini, Min-Jean Yin, Jeffrey Chen, Max Hallin, Karin Amundson, Shinji Yamazaki, David Romero, Aileen McHarg, Eileen Blasi, Yufeng Hong, Eileen Tompkins, Cynthia L. Palmer, Judith G. Deal, Brion W. Murray, James Solowiej, Michele McTigue, John Wickersham, Steven L. Bender · 发表于：Cancer Research · 年份：2007 · 被引用次数：9 · 研究领域：Angiogenesis and VEGF in Cancer、Cancer, Hypoxia, and Metabolism、PI3K/AKT/mTOR signaling in cancer

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 IC50s 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 (IC50 >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 concentra...