Development of 2, 4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy

Eur J Med Chem. 2017 May 5:131:1-13. doi: 10.1016/j.ejmech.2017.02.063. Epub 2017 Mar 8.

Abstract

Upon analysis of the reported crystal structure of PAK4 inhibitor KY04031 (PAK4 IC50 = 0.790 μM) in the active site of PAK4, we investigated the possibility of changing the triazine core of KY04031 to a quinazoline. Using KY04031 as a starting compound, a library of 2, 4-diaminoquinazoline derivatives were designed and synthesized. These compounds were evaluated for PAK4 inhibition, leading to the identification of compound 9d (PAK4 IC50 = 0.033 μM). Compound 9d significantly induced the cell cycle in the G1/S phase and inhibited migration and invasion of A549 cells that over-express PAK4 via regulation of the PAK4-LIMK1 signalling pathway. A docking study of compound 9d was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of PAK4 inhibitors. Compound 9d may serve as a lead compound for anticancer drug discovery and as a valuable research probe for further biological investigation of PAK4.

Keywords: 2,4-diaminoquinazoline; Anti-cancer; PAK4 inhibitor; Synthesis; p21-activated kinase.

MeSH terms

  • A549 Cells
  • Cell Cycle / drug effects
  • Cell Movement / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship
  • p21-Activated Kinases / antagonists & inhibitors*
  • p21-Activated Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • Quinazolines
  • 2,4-diaminoquinazoline
  • PAK4 protein, human
  • p21-Activated Kinases