학술논문
Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth
Document Type
Author abstract
Author
Murray, Brion W.; Guo, Chuangxing; Piraino, Joseph; Westwick, John K.; Zhang, Cathy; Lamerdin, Jane; Dagostino, Eleanor; Knighton, Daniel; Loi, Cho-Ming; Zager, Michael; Kraynov, Eugenia; Popoff, Ian; Christensen, James G.; Martinez, Ricardo; Kephart, Susan E.; Marakovits, Joseph; Karlicek, Shannon; Bergqvist, Simon; Smeal, Tod
Source
Proceedings of the National Academy of Sciences of the United States. May 18, 2010, Vol. 107 Issue 20, p9446, 6 p.
Subject
Language
English
ISSN
0027-8424
Abstract
Despite abundant evidence that aberrant Rho-family GTPase activation contributes to most steps of cancer initiation and progression, there is a dearth of inhibitors of their effectors (e.g., p21-activated kinases). Through high-throughput screening and structure-based design, we identify PF-3758309, a potent ([K.sub.d] = 2.7 nM), ATP-competitive, pyrrolopyrazole inhibitor of PAK4. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 ([IC.sub.50] = 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines ([IC.sub.50] = 4.7 [+ or -] 3 nM). The molecular underpinnings of PF-3758309 biological effects were characterized using an integration of traditional and emerging technologies. Crystallographic characterization of the PF-3758309/PAK4 complex defined determinants of potency and kinase selectivity. Global high-content cellular analysis confirms that PF-3758309 modulates known PAK4-dependent signaling nodes and identifies unexpected links to additional pathways (e.g., p53). In tumor models, PF-3758309 inhibits PAK4-dependent pathways in proteomic studies and regulates functional activities related to cell proliferation and survival. PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma [EC.sub.50] value of 0.4 nM in the most sensitive model. This study defines PAK4-related pathways, provides additional support for PAK4 as a therapeutic target with a unique combination of functions (apoptotic, cytoskeletal, cell-cycle), and identifies a potent, orally available small-molecule PAK inhibitor with significant promise for the treatment of human cancers. chemical biology | high-content screening | p53 | signaling signature doi: 10.1073/pnas.0911863107