PF-562271

A potent, ATP-competitive and reversible inhibitor of FAK and Pyk2 catalytic activity with IC50s of 1.5 nM and 14 nM, respectively.

This potent, yet reversible ATP-competitive protein kinase inhibitor (FWfreebase = 507.49 g/mol; CAS 717907-75-0; FWHCl-Salt = 543.95 g/mol; FW = 665.66 g/mol (benzenesulfonate salt); CAS 939791-38-5), also named, N- [3-[[[2-[(2,3-dihydro-2-oxo-1H-indol-5-yl)amino]-5-(trifluoromethyl)-4- pyrimidinyl]amino]methyl]-2-pyridinyl]-N-methylmethanesulfonamide, targets Focal Adhesion Kinase, or FAK, (IC50 = 1.5 nM), with about 10x greater potency than for Pyk2 (IC50 = 14 nM) and >100x more than for other protein kinases. PF-562271 binds within the ATP-binding cleft of FAK, where it forms two of the three “canonical” H-bonds between the inhibitor and main-chain atoms in the protein kinase’s hinge region. Mode of Inhibitory Action: Many cancer cells grow in an anchorage-independent manner, and the nonreceptor tyrosine kinase FAK is thought to contribute to this phenotype by localizing in focal adhesion plaques and has playing roles as a scaffolding and signaling component. Integrin signals within the tumor microenvironment also affect cancer cell survival and invasion during tumor progression, and FAK is activated by b-integrins in both normal and transformed cells. PF-562271 inhibits FAK phosphorylation in vivo in a dose-dependent fashion (calculated EC50 = 93 ng/mL) after p.o. administration to tumor-bearing mice. PF-562271 also has potent effects on metastatic prostate cancer growth in vivo. Oral administration of PF-562271 at a dose of 5 mg/kg suppressed the growth and local spread of intratibial tumors and restored tumor-induced bone loss. The unique ability of PF-562271 to both curb tumor growth and safely increase bone formation may be an effective therapy for many cancer patients with bone metastases and cancer-associated osteoporosis.