title: p21-activated kinase inhibitors.
abstract: The p21-activated kinases (PAKs) are Ser/Thr kinases in the STE20 kinase family with important roles in regulating cytoskeletal organization, cell migration, and signaling. The PAK enzyme family comprises six members subdivided into two groups: Group I, represented by PAK1, 2, and 3, and Group II, represented by PAK 4, 5, and 6, based on sequence and structural homology. Individual PAK isoforms were found to be overexpressed and amplified in a variety of human cancers, and in vitro and in vivo studies using genetically engineered systems as well as small-molecule tool compounds have suggested therapeutic utility of PAKs as oncology targets. The identification of potent and kinome-selective ATP-competitive PAK inhibitors has proven challenging, likely caused by the openness and unique plasticity of the ATP-binding site of PAK enzymes. Progress in achieving increased kinase selectivity has been achieved with certain inhibitors but at the expense of increased molecular weight. Allosteric inhibitors, such as IPA-3, leverage the unique Group I PAK autoregulatory domain for selective inhibition, and this approach might provide an outlet to evade the kinase selectivity challenges observed with ATP-competitive PAK inhibitors.
authors.affiliation: Genentech, Discovery Chemistry, South San Francisco, California, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.affiliation: Genentech, Discovery Chemistry, South San Francisco, California, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.affiliation: Genentech, Translational Oncology, South San Francisco, California, USA.
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. Electronic address: Jonathan.Chernoff@fccc.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
mesh_terms: D000818:Animals; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D054462:p21-Activated Kinases
keywords: ATP-competitive kinase inhibitors; Allosteric kinase inhibitors; Genomic amplification; Kinase selectivity; Ligand efficiency; Oncology; Overexpression; p21-activated kinases