title: Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme.
abstract: NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligases, and has been considered as an attractive molecular target for the development of drugs against cancer. A pharmacophore model constructed from a training set of deoxyvasicinone derivatives was used to screen 376 compounds from an analogue database. From the initial screening, the valine-linked deoxyvasicinone derivative 9 and the N-isopropyl-linked deoxyvasicinone derivative 10 emerged as the top scoring candidates. Compounds 9 and 10 showed micromolar potencies in both cell-free and cell-based systems, with selectivity for NAE over the related enzymes SAE and UAE. Molecular modelling analysis suggested that 9 and 10 may inhibit NAE by blocking the ATP-binding domain. Thus, these deoxyvasicinone derivatives could be considered as promising lead molecules for the development of more potent inhibitors of NAE.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Zhong
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Ka-Ho
authors.initials: KH
authors.lastname: Leung
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Sheng
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Daniel Shiu-Hin
authors.initials: DS
authors.lastname: Chan
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong.
authors.forename: Quan-Bin
authors.initials: QB
authors.lastname: Han
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong.
authors.forename: Sharon Lai-Fung
authors.initials: SL
authors.lastname: Chan
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong. Electronic address: edmondma@hkbu.edu.hk.
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: duncanleung@umac.mo.
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
mesh_terms: D045744:Cell Line, Tumor; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D000075687:NEDD8 Protein; D011799:Quinazolines / Q000737:chemistry*; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011799:Quinazolines; D014452:Ubiquitins; C025696:2,3-trimethylene-4-quinazolone
keywords: Deoxyvasicinone; Drug discovery; NEDD8; Pharmacophore; Ubiquitin-like