Discovery of 2-(4-Substituted-piperidin/piperazine-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-quinazoline-2,4-diamines as PAK4 Inhibitors with Potent A549 Cell Proliferation, Migration, and Invasion Inhibition Activity

Molecules. 2018 Feb 14;23(2):417. doi: 10.3390/molecules23020417.

Abstract

A series of novel 2,4-diaminoquinazoline derivatives were designed, synthesized, and evaluated as p21-activated kinase 4 (PAK4) inhibitors. All compounds showed significant inhibitory activity against PAK4 (half-maximal inhibitory concentration IC50 < 1 μM). Among them, compounds 8d and 9c demonstrated the most potent inhibitory activity against PAK4 (IC50 = 0.060 μM and 0.068 μM, respectively). Furthermore, we observed that compounds 8d and 9c displayed potent antiproliferative activity against the A549 cell line and inhibited cell cycle distribution, migration, and invasion of this cell line. In addition, molecular docking analysis was performed to predict the possible binding mode of compound 8d. This series of compounds has the potential for further development as PAK4 inhibitors for anticancer activity.

Keywords: 2,4-diaminoquinazoline; PAK4 inhibitor; anticancer; p21-activated kinase.

MeSH terms

  • A549 Cells
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology
  • p21-Activated Kinases / antagonists & inhibitors*
  • p21-Activated Kinases / genetics

Substances

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