期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 126, 期 -, 页码 1083-1106出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.12.026
关键词
Nek2 inhibitors; Imidazo[1,2-a]pyridine; Antitumor activity; Selectivity
资金
- National Natural Science Foundation of China [21572067]
- NSF of China [21332003]
- Science and Technology Commission of Shanghai Municipality [14431902700]
- Open Funds of State Key Laboratory of Oncology in South China [HN2016-03]
We present herein the discovery and development of novel and potent Nek2 inhibitors with distinctive in vitro and in vivo antitumor activity based on an imidazo[1,2-a]pyridine scaffold. Our studies identified a nonlinear SAR for activity against both Nek2 and cancer cells. Bioisostere and structure-based design techniques were employed to identify compounds 42c (MBM-17, IC50 = 3.0 nM) and 42g (MBM-55, IC50 = 1.0 nM), which displayed low nanomolar activity and excellent selectivity for Nek2. Both compounds effectively inhibited the proliferation of cancer cells by inducing cell cycle arrest and apoptosis. Importantly, the salts form of these two compounds (MBM-17S and MBM-55S) significantly suppressed tumor growth in vivo without apparent toxicity based on appearance and changes in body weight. In summary, MBM-17 and MBM-55 displayed the potential for substantial therapeutic application in cancer treatment. (C) 2016 Elsevier Masson SAS. All rights reserved.
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