Design, synthesis, screening, and molecular modeling study of a new series of ROS1 receptor tyrosine kinase inhibitors

被引：32

作者：

El-Deeb, Ibrahim M. ^{[2
]}

Park, Byung Sun ^{[3
,4
]}

Jung, Su Jin ^{[1
]}

Yoo, Kyung Ho ^{[1
]}

Oh, Chang-Hyun ^{[1
]}

Cho, Seung Joo ^{[5
,6
]}

Han, Dong Keun ^{[1
]}

Lee, Jae Yeol ^{[3
,4
]}

Lee, So Ha ^{[1
]}

机构：

[1] Korea Adv 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, Dept Cellular & Mol Med, Coll Med, Kwangju 501759, South Korea

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 19期

关键词：

Kinase inhibitors; ROS1; Glioblastoma multiforme; Homology modeling; Pyrazole; C-ROS; BIOLOGICAL EVALUATION; GENE-MUTATIONS; GLIOBLASTOMA; CANCER; EXPRESSION; PATHWAYS; POTENT;

D O I：

10.1016/j.bmcl.2009.08.029

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of rationally designed ROS1 tyrosine kinase inhibitors was synthesized and screened. Compound 12b has showed good potency with IC50 value of 209 nM, which is comparable with that of the reference lead compound 1. Molecular modeling studies have been performed, that is, a homology model for ROS1 was built, and the screened inhibitors were docked into its major identified binding site. The docked poses along with the activity data have revealed a group of the essential features for activity. Overall, simplification of the lead compound 1 into compound 12b has maintained the activity, while facilitated the synthetic advantages. A molecular interaction model for ROS1 kinase and inhibitors has been proposed. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：5622 / 5626

页数：5

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