2. Academic Validation
  3. Discovery of benzothiazole derivatives as novel non-sulfamide NEDD8 activating enzyme inhibitors by target-based virtual screening

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

  • Eur J Med Chem. 2017 Jun 16;133:174-183. doi: 10.1016/j.ejmech.2017.03.076.
Hao Ma 1,  Chunlin Zhuang 2,  Xiguo Xu 3,  Jiao Li 2,  Juan Wang 4,  Xiao Min 2,  Wannian Zhang 5,  Huojun Zhang 6,  Zhenyuan Miao 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 2 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 3 School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
  • 4 Center for Pharmacological Evaluation and Research, Shanghai Institute of Pharmaceutical Industry, 1111 Zhongshanbeiyi Road, Shanghai 200437, China.
  • 5 School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: [email protected].
  • 6 Shanghai Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China. Electronic address: [email protected].
  • 7 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: [email protected].
PMID: 28388520 DOI: 10.1016/j.ejmech.2017.03.076
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.

Keywords

Benzothiazoles; NAE inhibitors; Virtual screening.

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