Document Type

Journal Article

Department/Unit

School of Chinese Medicine

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.

Publication Year

2015

Journal Title

Methods

Volume number

71

Publisher

Elsevier

First Page (page number)

71

Last Page (page number)

76

Referreed

1

DOI

10.1016/j.ymeth.2014.08.014

ISSN (print)

10462023

Link to Publisher’s Edition

http://dx.doi.org/10.1016/j.ymeth.2014.08.014

Keywords

Drug discovery, Ubiquitin-like, NEDD8, Deoxyvasicinone, Pharmacophore

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