Discovery of novel Bcr-Abl inhibitors targeting myristoyl pocket and ATP site

Bioorg Med Chem. 2014 Dec 15;22(24):6876-84. doi: 10.1016/j.bmc.2014.10.030. Epub 2014 Oct 27.

Abstract

Bcr-Abl plays an essential role in the pathogenesis and development of chronic myeloid leukaemia (CML). Inhibition of Bcr-Abl has great potential for therapeutic intervention in CML. In order to obtain novel and potent Bcr-Abl inhibitors, twenty seven 4,6-disubstituted pyrimidines were synthesized and evaluated herein. The biological results indicated that four compounds of them (C4, C5, C16, and C23) were potent Bcr-Abl inhibitors which were comparable to positive control. Moreover, C4 and C5 displayed promising antiproliferative activity against K562 cells. The results suggested that these 4,6-disubstituted pyrimidines could serve as promising leads for further optimization of Bcr-Abl inhibitors.

Keywords: ATP-binding site; Allosteric pocket; Bcr–Abl; Inhibitors; Myristoyl pocket.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Allosteric Regulation
  • Binding Sites
  • Cell Proliferation / drug effects
  • Drug Evaluation, Preclinical
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • K562 Cells
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / toxicity
  • Protein Structure, Tertiary
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / toxicity

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Adenosine Triphosphate
  • Fusion Proteins, bcr-abl