title: An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase.
abstract: Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation. We developed a screen for allosteric inhibitors targeting Pak1 activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak.
authors.affiliation: Basic Sciences Division, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Sean W
authors.initials: SW
authors.lastname: Deacon
authors.forename: Alexander
authors.initials: A
authors.lastname: Beeser
authors.forename: Jami A
authors.initials: JA
authors.lastname: Fukui
authors.forename: Ulrike E E
authors.initials: UE
authors.lastname: Rennefahrt
authors.forename: Cynthia
authors.initials: C
authors.lastname: Myers
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Peterson
mesh_terms: D000818:Animals; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D009284:Naphthols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D004220:Disulfides; C541795:IPA-3 compound; D007527:Isoenzymes; D009284:Naphthols; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D054462:p21-Activated Kinases