Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Brent D. G. Page (), Nicholas C. K. Valerie, Roni H. G. Wright, Olov Wallner, Rebecka Isaksson, Megan Carter, Sean G. Rudd, Olga Loseva, Ann-Sofie Jemth, Ingrid Almlöf, Jofre Font-Mateu, Sabin Llona-Minguez, Pawel Baranczewski, Fredrik Jeppsson, Evert Homan, Helena Almqvist, Hanna Axelsson, Shruti Regmi, Anna-Lena Gustavsson, Thomas Lundbäck, Martin Scobie, Kia Strömberg, Pål Stenmark, Miguel Beato and Thomas Helleday ()
Additional contact information
Brent D. G. Page: Karolinska Institutet
Nicholas C. K. Valerie: Karolinska Institutet
Roni H. G. Wright: Barcelona Institute for Science and Technology
Olov Wallner: Karolinska Institutet
Rebecka Isaksson: Karolinska Institutet
Megan Carter: Stockholm University
Sean G. Rudd: Karolinska Institutet
Olga Loseva: Karolinska Institutet
Ann-Sofie Jemth: Karolinska Institutet
Ingrid Almlöf: Karolinska Institutet
Jofre Font-Mateu: Barcelona Institute for Science and Technology
Sabin Llona-Minguez: Karolinska Institutet
Pawel Baranczewski: Uppsala University
Fredrik Jeppsson: Karolinska Institutet
Evert Homan: Karolinska Institutet
Helena Almqvist: Karolinska Institutet
Hanna Axelsson: Karolinska Institutet
Shruti Regmi: Karolinska Institutet
Anna-Lena Gustavsson: Karolinska Institutet
Thomas Lundbäck: Karolinska Institutet
Martin Scobie: Karolinska Institutet
Kia Strömberg: Karolinska Institutet
Pål Stenmark: Stockholm University
Miguel Beato: Barcelona Institute for Science and Technology
Thomas Helleday: Karolinska Institutet

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02293-7

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DOI: 10.1038/s41467-017-02293-7

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