Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors

Byung Sun Park, Mohammad M. Al-Sanea, Ahmed Z. Abdelazem, Hye Mi Park, Eun Joo Roh, Hyun Mee Park, Kyung Ho Yoo, Taebo Sim, Jin Sung Tae, So Ha Lee

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Abstract

Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC50 values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC50 values in the enzymatic assay, which are from 13.6 to 283 nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC50 = 13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value = 0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 μM.

Original languageEnglish
Pages (from-to)3871-3878
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number15
DOIs
Publication statusPublished - 2014 Aug 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Park, B. S., Al-Sanea, M. M., Abdelazem, A. Z., Park, H. M., Roh, E. J., Park, H. M., Yoo, K. H., Sim, T., Tae, J. S., & Lee, S. H. (2014). Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors. Bioorganic and Medicinal Chemistry, 22(15), 3871-3878. https://doi.org/10.1016/j.bmc.2014.06.020