Design, synthesis and biological evaluation of 2-indolinone derivatives as PAK1 inhibitors in MDA-MB-231 cells

Bioorg Med Chem Lett. 2020 Sep 1;30(17):127355. doi: 10.1016/j.bmcl.2020.127355. Epub 2020 Jun 20.

Abstract

P21-activated kinase 1 (PAK1) plays a vital role in the proliferation, survival and migration of cancer cells, which has emerged as a promising drug target for cancer therapy. In this study, a series of 2-indolinone derivatives were designed and synthesized through a structure-based strategy. A potent PAK1 inhibitor (ZMF-005) was discovered, which presented an IC50 value of 0.22 μM against PAK1 with potent antiproliferative activity. Furthermore, we predicted the binding mode of ZMF-005 and PAK1 by molecule docking and dynamic (MD) simulation. In addition, ZMF-005 was documented to induce significant apoptosis and suppress migration in MDA-MB-231 cells. Collectively, these findings revealed that ZMF-005 is a novel potent PAK1 inhibitor for breast cancer treatment.

Keywords: Apoptosis; Breast cancer; Migration; Molecule docking; PAK1 inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Binding Sites
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Drug Design*
  • Female
  • Humans
  • Molecular Docking Simulation
  • Oxindoles / chemistry*
  • Oxindoles / metabolism
  • Oxindoles / pharmacology
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Thermodynamics
  • p21-Activated Kinases / antagonists & inhibitors*
  • p21-Activated Kinases / metabolism

Substances

  • Oxindoles
  • Protein Kinase Inhibitors
  • 2-oxindole
  • PAK1 protein, human
  • p21-Activated Kinases