Design, synthesis, and biological activity of phenyl-pyrazole derivatives as BCR-ABL kinase inhibitors

Bioorg Med Chem. 2015 Jul 1;23(13):3147-52. doi: 10.1016/j.bmc.2015.04.083. Epub 2015 May 12.

Abstract

4-(Pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives have been proposed as new BCR-ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. In the present study, a series of 4-(pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives were synthesized and their activities against BCR-ABL1 kinase in vitro were evaluated by using Kinase-Glo assay. All new compounds showed from moderate to potent activities against wild-type (wt) BCR-ABL1 kinase with an IC50 range from 14.2 to 326.0nM. Among them, seven compounds exhibited BCR-ABL1 kinase inhibitory activities with IC50 values less than 50nM. Compound 7a displayed the most potent inhibitory activity to BCR-ABL kinase (IC50: 14.2nM). Docking simulation was performed for compounds 7a and 7i into the BCR-ABL kinase structure active site to determine the probable binding model. The preliminary structure-activity relationship was discussed. The interesting activities of these compounds may make them promising candidates as therapeutic agents for chronic myelogenous leukemia.

Keywords: BCR–ABL; Molecular docking; Phenyl-pyrazole; Tyrosine kinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Benzene Derivatives / chemical synthesis*
  • Benzene Derivatives / pharmacology
  • Catalytic Domain
  • Cell Line, Tumor
  • Combinatorial Chemistry Techniques
  • Drug Design
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / chemistry
  • Fusion Proteins, bcr-abl / genetics
  • Gene Expression
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • BCR-ABL1 fusion protein, human
  • Benzene Derivatives
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Fusion Proteins, bcr-abl