p21-Activated kinases (PAKs) are STE20 serine/threonine kinases that are vital to normal cell function. Binding of various upstream partners to PAKs results in release of an autoinhibitory domain that blocks activity of the kinase domain. PAKs are upregulated in several human cancers and are potential therapeutic targets for cancer intervention. PF-3758309 is an ATP-competitive inhibitor of PAK4, preventing the phosphorylation of the PAK4 substrate GEF-H1 (IC50 = 1.3 nM) and blocking anchorage-independent growth of a panel of tumor cell lines (IC50 = 4.7 nM). It also inhibits the ability of kinase domains from other PAKs to phosphorylate peptide substrates (Kis = 18.1, 17.1, 13.7, 190, and 99 nM for PAKs 5, 6, 1, 2, and 3, respectively). PF-3758309 blocks the growth of multiple human tumor xenografts.
