Download MendeleySmall-Molecule P21-Activated Kinase Inhibitor Pf- 3758309 is a Potent Inhibitor of Oncogenic Signaling and Tumor Growth.
Murray, B., Guo, C., Piraino, J., Westwick, J., Zhang, C., Lamerdin, J., Dagostino, E., Knighton, D.R., Loi, C.-M., Zager, M., Kraynov, E., Popoff, I., Christensen, J., Martinez, R., Kephart, S., Marakovits, J., Karlicek, S., Bergqvist, S., Smeal, T.(2010) Proc Natl Acad Sci U S A 107: 9446
- PubMed: 20439741
- DOI: https://doi.org/10.1073/pnas.0911863107
- Primary Citation of Related Structures:
2X4Z - PubMed 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(d) = 2.7 nM), ATP-competitive, pyrrolopyrazole inhibitor of PAK4. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC(50) = 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC(50) = 4.7 +/- 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(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.
Organizational Affiliation:
Pfizer Oncology, Pfizer, San Diego, CA 92121, USA. [email protected]
