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Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells
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Number of Authors: 252018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 250Article in journal (Refereed) Published
Abstract [en]

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 ADPribose 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.

Place, publisher, year, edition, pages
2018. Vol. 9, article id 250
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Cell Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
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URN: urn:nbn:se:su:diva-152723DOI: 10.1038/s41467-017-02293-7ISI: 000422650500001PubMedID: 29343827OAI: oai:DiVA.org:su-152723DiVA, id: diva2:1185611
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26Bibliographically approved

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Carter, MeganStenmark, Pål
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