Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Abstract

With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.

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Item Type:	Article
Authors/Creators:	Page, B.D.G. Valerie, N.C.K. Wright, R.H.G. Wallner, O. Isaksson, R. Carter, M. Rudd, S.G. Loseva, O. Jemth, A.-S. Almlöf, I. Font-Mateu, J. Llona-Minguez, S. Baranczewski, P. Jeppsson, F. Homan, E. Almqvist, H. Axelsson, H. Regmi, S. Gustavsson, A.-L. Lundbäck, T. Scobie, M. Strömberg, K. Stenmark, P. Beato, M. Helleday, T. https://orcid.org/0000-0002-7384-092X
Copyright, Publisher and Additional Information:	© The Author(s) 2017. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 17 November 2017 Published (online): 17 January 2018 Published: 17 January 2018
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	08 Apr 2020 15:23
Last Modified:	08 Apr 2020 15:37
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41467-017-02293-7
Related URLs:	Author Erratum/Corrigendum
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:159271

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Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

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