Discovery of benzothiazole derivatives as novel non-sulfamide NEDD8 activating enzyme inhibitors by target-based virtual screening

• DOI: 10.1016/j.ejmech.2017.03.076
• Publication Date: 2017-03-31T05:17:19Z
• Authors: Hao Ma; Chunlin Zhuang; Xiguo Xu; Jiao Li; Juan Wang; Xiao Min; Wannian Zhang; Huojun Zhang; Zhenyuan Miao
• Keywords: Sulfamide; Benzothiazole; NEDD8; IC50; Structure–activity relationship

NEDD8 activating enzyme (NAE) plays a critical role in various cellular functions in cancers. In this study, a target-based virtual screening was applied to discover benzothiazoles to be potent non-covalent NAE inhibitors. Further two round optimizations concluded a preliminary structure-activity relationship (SAR) of their derivatives. Three compounds (6k, 7b, ZM223) exhibited antitumor activities in nanomolar range. ZM223 showed excellent anticancer activity against HCT116 colon cancer cells with an IC50 value of 100 nM. Mechanistically, compounds 6k, 7b, and ZM223 caused a dose-response decrease in the level of NEDD8 and an increase in the downstream UBC12 protein. This scaffold represents a promising lead for developing non-sulfamide NAE inhibitors.