Allosteric targeting of the Fanconi anemia ubiquitin-conjugating enzyme Ube2T by fragment screening

Morreale, F. E., Bortoluzzi, A., Chaugule, V. K., Arkinson, C., Walden, H. and Ciulli, A. (2017) Allosteric targeting of the Fanconi anemia ubiquitin-conjugating enzyme Ube2T by fragment screening. Journal of Medicinal Chemistry, 60(9), pp. 4093-4098. (doi: 10.1021/acs.jmedchem.7b00147) (PMID:28437106) (PMCID:PMC5441753)

[img]
Preview
Text
149793.pdf - Published Version
Available under License Creative Commons Attribution.

4MB

Abstract

Ube2T is the E2 ubiquitin-conjugating enzyme of the Fanconi anemia DNA repair pathway and it is overexpressed in several cancers, representing an attractive target for the development of inhibitors. Despite the extensive efforts in targeting the ubiquitin system, very few E2 binders have currently been discovered. Herein we report the identification of a new allosteric pocket on Ube2T through a fragment screening using biophysical methods. Several fragments binding to this site inhibit ubiquitin conjugation in vitro.

Item Type:Articles
Additional Information:This work was supported by the European Research Council (ERC-2012-StG-311460 DrugE3CRLs starting grant to A.C.; ERC-2015-CoG-681582 ICLUb consolidator grant to H.W.); the UK Biotechnology and Biological Sciences Research Council (BBSRC BB/G023123/2 David Phillips Fellowship to A.C.); the Medical Research Council (MRC grant number MC_UU_12016/12); the EMBO Young Investigator Programme to H.W.; and the Wellcome Trust (strategic awards 100476/Z/12/Z for biophysics and drug discovery and 094090/Z/10/Z for structural biology and X-ray crystallography to BCDD).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Chaugule, Dr Viduth and Arkinson, Connor and Walden, Professor Helen
Authors: Morreale, F. E., Bortoluzzi, A., Chaugule, V. K., Arkinson, C., Walden, H., and Ciulli, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Journal of Medicinal Chemistry
Publisher:American Chemical Society
ISSN:0022-2623
ISSN (Online):1520-4804
Published Online:24 April 2017
Copyright Holders:Copyright © 2017 American Chemical Societ
First Published:First published in Journal of Medicinal Chemistry 60(9):4093-4098
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record