1. Academic Validation
  2. Design, synthesis, and biological activity of phenyl-pyrazole derivatives as BCR-ABL kinase inhibitors

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.
Liming Hu 1 Yuyan Zheng 2 Zhipeng Li 2 Yujie Wang 2 Yongjuan Lv 2 Xuemei Qin 2 Chengchu Zeng 2
Affiliations

Affiliations

  • 1 College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China. Electronic address: huliming@bjut.edu.cn.
  • 2 College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China.
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.

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