Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain

Exp Mol Med. 2016 Apr 29;48(4):e229. doi: 10.1038/emm.2016.13.

Abstract

p21-activated kinases (PAKs) are key regulators of actin dynamics, cell proliferation and cell survival. Deregulation of PAK activity contributes to the pathogenesis of various human diseases, including cancer and neurological disorders. Using an ELISA-based screening protocol, we identified naphtho(hydro)quinone-based small molecules that allosterically inhibit PAK activity. These molecules interfere with the interactions between the p21-binding domain (PBD) of PAK1 and Rho GTPases by binding to the PBD. Importantly, they inhibit the activity of full-length PAKs and are selective for PAK1 and PAK3 in vitro and in living cells. These compounds may potentially be useful for determining the details of the PAK signaling pathway and may also be used as lead molecules in the development of more selective and potent PAK inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Cell Line
  • Drug Discovery / methods
  • Drug Evaluation, Preclinical / methods
  • Enzyme Activation / drug effects
  • Humans
  • Isoenzymes
  • Protein Binding
  • Protein Interaction Domains and Motifs*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Small Molecule Libraries
  • Structure-Activity Relationship
  • cdc42 GTP-Binding Protein / metabolism
  • p21-Activated Kinases / antagonists & inhibitors*
  • p21-Activated Kinases / chemistry
  • p21-Activated Kinases / metabolism*

Substances

  • Isoenzymes
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • p21-Activated Kinases
  • cdc42 GTP-Binding Protein