Design, synthesis and biological evaluation of new potent and highly selective ROS1-tyrosine kinase inhibitor

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Park, Byung Sun^3,4  El-Deeb, Ibrahim M.²  Yoo, Kyung Ho¹  Oh, Chang-Hyun¹  Cho, Seung Joo^5,6  Han, Dong Keun¹  Lee, Hye-Seung⁷  Lee, Jae Yeol^3,4  Lee, So Ha¹ 

[1] Korea Inst Sci & Technol, Life Sci Res Div, Seoul 130650, South Korea

[2] Univ Sci & Technol, Dept Biomol Sci, Taejon 305333, South Korea

[3] Kyung Hee Univ, Res Inst Basic Sci, Coll Sci, Seoul 130701, South Korea

[4] Kyung Hee Univ, Dept Chem, Coll Sci, Seoul 130701, South Korea

[5] Chosun Univ, Res Ctr Resistant Cells, Kwangju 501759, South Korea

[6] Chosun Univ, Coll Med, Dept Cellular & Mol Med, Kwangju 501759, South Korea

[7] Korea Ocean Res & Dev Inst, Marine Nat Prod Lab, Seoul 425600, South Korea

关键词: ROS1;    Tyrosine kinase;    Kinase inhibitor;    Astrocytoma;    Glioblastoma multiforme;    Pyrazole;    Selectivity;    Cancer;   

DOI  :  10.1016/j.bmcl.2009.06.066

来源: Elsevier

【 摘 要 】

ROS1 protein is a receptor tyrosine kinase that has been reported mainly in meningiomas and astrocytomas, and until now, there is no selective inhibitor for this kinase. In this study, we illustrate for the synthesis of a highly potent and selective inhibitor for ROS1 kinase. The synthesized compound 1 was tested initially at a single dose concentration of 10 mu M over 45 different kinases. At this concentration, a 94% inhibition of the enzymatic activity of ROS1 kinase was observed, while the inhibition in activity was below 30% in all of the other kinases. The pyrazole compound 1 was further tested in a 10-dose IC50 mode and showed an IC50 value of 199 nM for ROS1 kinase. The compound 1 can be used as a promising lead for the development of new selective inhibitors for ROS1 kinase, and it may open the way for new selective therapeutics for astrocytomas. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

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