Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

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  • dc.contributor.author Page, Brent D.G.
  • dc.contributor.author Wright, Roni H.G.
  • dc.contributor.author Font Mateu, Jofre, 1977-
  • dc.contributor.author Beato, Miguel
  • dc.contributor.author Helleday, Thomas
  • dc.date.accessioned 2019-11-26T07:53:51Z
  • dc.date.available 2019-11-26T07:53:51Z
  • dc.date.issued 2018
  • dc.description.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.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Page BDG, Valerie NCK, Wright RHG, Wallner O, Isaksson R, Carter M et al. Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells. Nat Commun. 2018;9(1):250. DOI: 10.1038/s41467-017-02293-7
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-017-02293-7
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/42975
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nature Communications. 2018;9(1):250
  • dc.rights © 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/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Breast cancer
  • dc.subject.keyword Drug discovery and development
  • dc.subject.keyword Screening
  • dc.subject.keyword Target validation
  • dc.title Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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Articles (Departament de Medicina i Ciències de la Vida)