Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/16924
Title: Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme
Authors: Zhong, HJ
Leung, KH
Lin, S
Chan, DSH
Han, QB
Chan, SLF 
Ma, DL
Leung, CH
Keywords: Deoxyvasicinone
Drug discovery
NEDD8
Pharmacophore
Ubiquitin-like
Issue Date: 2015
Publisher: Academic Press Inc.
Source: Methods, 2015, v. 71, no. C, p. 71-76 How to cite?
Journal: Methods 
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.
URI: http://hdl.handle.net/10397/16924
ISSN: 1046-2023
DOI: 10.1016/j.ymeth.2014.08.014
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