2X4Z

Crystal Structure of the Human p21-Activated Kinase 4 in Complex with PF-03758309

Summary for 2X4Z

• Entry DOI: 10.2210/pdb2x4z/pdb
• Related: 2BVA 2CDZ 2J0I
• Descriptor: SERINE/THREONINE-PROTEIN KINASE PAK 4, GLYCEROL, PF-3758309, ... (4 entities in total)
• Functional Keywords: transferase, nucleotide-binding atp-binding, phosphoprotein
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 34099.65

Authors

Knighton, D.R.,Deng, Y.,Murray, B.,Guo, C.,Piraino, J.,Westwick, J.,Zhang, C.,Lamerdin, J.,Dagostino, E.,Loi, C.-M.,Zager, M.,Kraynov, E.,Christensen, J.,Martinez, R.,Kephart, S.,Marakovits, J.,Karlicek, S.,Bergqvist, S.,Smeal, T. (deposition date: 2010-02-03, release date: 2010-05-19, Last modification date: 2024-11-13)

Primary citation

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.
Small-Molecule P21-Activated Kinase Inhibitor Pf- 3758309 is a Potent Inhibitor of Oncogenic Signaling and Tumor Growth.
Proc.Natl.Acad.Sci.USA, 107:9446-, 2010

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.

PubMed: 20439741
DOI: 10.1073/PNAS.0911863107

Experimental method

X-RAY DIFFRACTION (2.1 Å)