Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells
Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, SE-17121 Solna, Sweden..
Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, SE-17121 Solna, Sweden..
Barcelona Inst Sci & Technol, CRG, E-09003 Barcelona, Spain.;Univ Pompeu Fabra, E-08003 Barcelona, Spain..
Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, SE-17121 Solna, Sweden..
Show others and affiliations
2018 (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
NATURE PUBLISHING GROUP , 2018. Vol. 9, article id 250
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-343370DOI: 10.1038/s41467-017-02293-7ISI: 000422650500001PubMedID: 29343827OAI: oai:DiVA.org:uu-343370DiVA, id: diva2:1186291
Funder
Göran Gustafsson Foundation for Research in Natural Sciences and MedicineTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationSwedish Cancer SocietyWenner-Gren FoundationsÅke Wiberg FoundationSwedish Society for Medical Research (SSMF)Swedish Research CouncilAvailable from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-02-28Bibliographically approved

Open Access in DiVA

fulltext(2690 kB)24 downloads
File information
File name FULLTEXT01.pdfFile size 2690 kBChecksum SHA-512
1966d21196ab5b808ed090c6e5d0e22cbc2f7e4e34d26f0ebb0da9d85fab27971bc0c13148eef57679a63cc03c1d6987d12b7024384d80236123145764486046
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Baranczewski, Pawel
By organisation
Department of Pharmacy
In the same journal
Nature Communications
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 24 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 11 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf