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

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


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
Issue number15
Publication statusPublished - 2014 Aug 1

Bibliographical note

Funding Information:
This research was supported by Korea Institute of Science and Technology ( 2E22760 ) and a Grant (NRF-2011-0028676) from the creative/challenging research program of National Research Foundation of Korea. We also appreciate to Reaction Biology Corporation and DiscoveRx Corporation for kinase screening.


  • Cancer
  • Kinase inhibitor
  • ROS1
  • Structure-activity relationship
  • Suzuki coupling

ASJC Scopus subject areas

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


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