期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 148, 期 -, 页码 397-409出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.02.049
关键词
Autotaxin; Cancer; ATX inhibitors; Molecular docking; Pharmacokinetics
资金
- Basic Science Research Program through the National Research Foundation of Korea(NRF) - Ministry of Science, ICT & Future Planning [2017R1A284002827]
Autotaxin (ATX) is a potential target for the treatment of various cancers. A new series of ATX inhibitors was rationally designed and synthesized based on our previous study. Biological evaluation and structure-activity relationship (SAR) of this series are discussed. Among fourteen synthesized derivatives, six compounds (2, 3,4,12,13 and 14) exhibited enhanced ATX inhibitory activities with IC50 values in the low nanomolar range. Molecular interactions of all the synthesized compounds within the active site of ATX were studied through molecular docking studies. Herein, we describe our lead optimization efforts that resulted in the identification of a potent ATX inhibitor (compound 4 with IC50 = 1.23 nM, FS-3 and 2.18 nM, bis-pNPP). Furthermore, pharmacokinetic properties of this most promising compound are profiled. (C) 2018 Elsevier Masson SAS. All rights reserved.
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