2. Academic Validation
  3. Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

  • Nat Commun. 2018 Jan 17;9(1):250. doi: 10.1038/s41467-017-02293-7.
Brent D G Page 1,  Nicholas C K Valerie 2,  Roni H G Wright 3 4,  Olov Wallner 2,  Rebecka Isaksson 2,  Megan Carter 5,  Sean G Rudd 2,  Olga Loseva 2,  Ann-Sofie Jemth 2,  Ingrid Almlöf 2,  Jofre Font-Mateu 3 4,  Sabin Llona-Minguez 2,  Pawel Baranczewski 6,  Fredrik Jeppsson 2,  Evert Homan 2,  Helena Almqvist 7,  Hanna Axelsson 7,  Shruti Regmi 7,  Anna-Lena Gustavsson 7,  Thomas Lundbäck 7,  Martin Scobie 2,  Kia Strömberg 2,  Pål Stenmark 5,  Miguel Beato 3 4,  Thomas Helleday 8
Affiliations

Affiliations

  • 1 Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, SE-171 21, Sweden. [email protected].
  • 2 Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, SE-171 21, Sweden.
  • 3 Centre de Regulació Genòmica (CRG), Barcelona Institute for Science and Technology, Barcelona, E-09003, Spain.
  • 4 Universitat Pompeu Fabra, Barcelona, E-08003, Spain.
  • 5 Department of Biochemistry and Biophysics, Stockholm University, Stockholm, SE-106 91, Sweden.
  • 6 Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, Uppsala, SE-751 23, Sweden.
  • 7 Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, SE-171 21, Sweden.
  • 8 Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, SE-171 21, Sweden. [email protected].
PMID: 29343827 DOI: 10.1038/s41467-017-02293-7
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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