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 journalArticle

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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

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Inhibitory Concentration 50
Phosphotransferases
Molecular modeling
Cholangiocarcinoma
Enzyme Assays
Glioblastoma
Bioactivity
Scaffolds
Non-Small Cell Lung Carcinoma
Assays
Screening
Adenosine Triphosphate
Binding Sites
Cells
Enzymes
pyrazole
crizotinib

ASJC Scopus subject areas

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

Cite this

Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors. / Park, Byung Sun; Al-Sanea, Mohammad M.; Abdelazem, Ahmed Z.; Park, Hye Mi; Roh, Eun Joo; Park, Hyun Mee; Yoo, Kyung Ho; Sim, Taebo; Tae, Jin Sung; Lee, So Ha.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 15, 01.08.2014, p. 3871-3878.

Research output: Contribution to journalArticle

Park, BS, Al-Sanea, MM, Abdelazem, AZ, Park, HM, Roh, EJ, Park, HM, Yoo, KH, Sim, T, Tae, JS & Lee, SH 2014, 'Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors', Bioorganic and Medicinal Chemistry, vol. 22, no. 15, pp. 3871-3878. https://doi.org/10.1016/j.bmc.2014.06.020
Park, Byung Sun ; Al-Sanea, Mohammad M. ; Abdelazem, Ahmed Z. ; Park, Hye Mi ; Roh, Eun Joo ; Park, Hyun Mee ; Yoo, Kyung Ho ; Sim, Taebo ; Tae, Jin Sung ; Lee, So Ha. / Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 15. pp. 3871-3878.
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