Discovery of a novel NEDD8 Activating Enzyme Inhibitor with Piperidin-4-amine Scaffold by Structure-Based Virtual Screening

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• 作者：Peng Lu ; Xiaoxin Liu ; Xinrui Yuan ; Minfang He ; Yubin Wang ; Qi Zhang ; Ping-kai Ouyang
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：July 15, 2016
• 年：2016
• 卷：11
• 期：7
• 页码：1901-1907
• 全文大小：409K
• 年卷期：0
• ISSN：1554-8937

文摘

NEDD8 activating enzyme (NAE) plays an important role in regulating intracellular proteins with key parts in a broad array of cellular functions. Here, we report a structure-based virtual screening of a compound library containing 50 000 small molecular entities against the active site of NAE. Computational docking and scoring followed by biochemical screening and target validation lead to the identification of 1-benzyl-N-(2,4-dichlorophenethyl) piperidin-4-amine (M22) as a selective NAE inhibitor. M22 is reversible for NAE, inhibits multiple cancer cell lines with GI₅₀ values in the low micromolar range, and induces apoptosis in A549 cells. Furthermore, it produces tumor inhibition in AGS xenografts in nude mice and low acute toxicity in a zebrafish model. M22, a novel NAE inhibitor, represents a promising lead structure for the development of new antitumor agents.