Synthesis and biological evaluation of novel dasatinib analogues as potent DDR1 and DDR2 kinase inhibitors

Chem Biol Drug Des. 2017 Mar;89(3):420-427. doi: 10.1111/cbdd.12863. Epub 2016 Oct 17.

Abstract

Novel dasatinib analogues as DDR1 and DDR2 inhibitors were designed and synthesized. The synthesized compounds were screened for DDR1 and DDR2 kinase inhibitory and cancer cell proliferation inhibitory activities. Some of the compounds showed the potent inhibitory activities against both DDR1 and DDR2, as well as anticancer activity in low nanomolar range against K562 cell line; especially, compound 3j demonstrated significantly better inhibitory potency than the parental dasatinib against both DDRs and also demonstrated the potent inhibitory activity against K562 cell lines (IC50 values of 2.26±0.46 nm for DDR1, 7.04±2.90 nm for DDR2, and 0.125±0.017 nm for K562 cell line).

Keywords: DDR1; DDR2; anticancer activity; dasatinib; kinase inhibitor.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Proliferation / drug effects
  • Chemistry Techniques, Synthetic
  • Dasatinib / analogs & derivatives*
  • Dasatinib / metabolism
  • Discoidin Domain Receptor 1 / antagonists & inhibitors*
  • Discoidin Domain Receptor 1 / metabolism
  • Discoidin Domain Receptor 2 / antagonists & inhibitors*
  • Discoidin Domain Receptor 2 / metabolism
  • Drug Screening Assays, Antitumor
  • Humans
  • Hydrogen Bonding
  • K562 Cells / drug effects
  • Molecular Docking Simulation
  • Piperazine
  • Piperazines / chemistry
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Antineoplastic Agents
  • Piperazines
  • Protein Kinase Inhibitors
  • Piperazine
  • DDR1 protein, human
  • DDR2 protein, human
  • Discoidin Domain Receptor 1
  • Discoidin Domain Receptor 2
  • Dasatinib