Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

Ahmed Z. Abdelazem, Mohammad M. Al-Sanea, Byung Sun Park, Hye Mi Park, Kyung Ho Yoo, Taebo Sim, Jong Bae Park, Seung Hoon Lee, So Ha Lee

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds.

Original languageEnglish
Pages (from-to)195-208
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume90
DOIs
Publication statusPublished - 2015 Jan 27

Keywords

  • Non-small cell lung cancer
  • Pyrazol-4-ylpyrimidine
  • Receptor tyrosine kinase
  • ROS1 kinase inhibitor

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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  • Cite this

    Abdelazem, A. Z., Al-Sanea, M. M., Park, B. S., Park, H. M., Yoo, K. H., Sim, T., Park, J. B., Lee, S. H., & Lee, S. H. (2015). Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors. European Journal of Medicinal Chemistry, 90, 195-208. https://doi.org/10.1016/j.ejmech.2014.11.023