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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 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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Ma H,Zhuang C,Xu X,Li J,Wang J,Min X,Zhang W,Zhang H,Miao Z

doi

10.1016/j.ejmech.2017.03.076

subject

Has Abstract

pub_date

2017-06-16 00:00:00

pages

174-183

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(17)30244-1

journal_volume

133

pub_type

杂志文章

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