Design,synthesis, screening,and molecular modeling study of a new series of ROS1 receptor tyrosine kinase inhibitors |
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| Authors: | Ibrahim M El-Deeb Byung Sun Park Su Jin Jung Kyung Ho Yoo Chang-Hyun Oh Seung Joo Cho Dong Keun Han Jae Yeol Lee So Ha Lee |
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| Institution: | 1. Life Sciences Research Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea;2. Department of Biomolecular Science, University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea;3. Research Institute for Basic Sciences and Department of Chemistry, College of Science, Kyung Hee University, Seoul 130-701, Republic of Korea;4. Research Center for Resistant Cells, Chosun University, Gwangju 501-759, Republic of Korea;5. Department of Cellular and Molecular Medicine, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu Gwangju 501-759, Republic of Korea |
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| Abstract: | 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. |
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