Document Type

Journal Article

Department/Unit

School of Chinese Medicine

Title

Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme

Language

English

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.

Keywords

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

Publication Date

1-31-2015

Source Publication Title

Methods

Volume

71

Start Page

71

End Page

76

Publisher

Elsevier

Peer Reviewed

1

DOI

10.1016/j.ymeth.2014.08.014

Link to Publisher's Edition

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

ISSN (print)

10462023

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