title: Discovery of benzothiazole derivatives as novel non-sulfamide NEDD8 activating enzyme inhibitors by target-based virtual screening.
abstract: 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 IC50value 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.
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ma
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Xiguo
authors.initials: X
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Pharmacological Evaluation and Research, Shanghai Institute of Pharmaceutical Industry, 1111 Zhongshanbeiyi Road, Shanghai 200437, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Min
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: zhangwnk@hotmail.com.
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China. Electronic address: chyyzhj@163.com.
authors.forename: Huojun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: miaozhenyuan@hotmail.com.
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human
keywords: Benzothiazoles; NAE inhibitors; Virtual screening