Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-02293-7
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Funding
- Goran Gustafsson Foundation
- Swedish Pain Relief Foundation
- Thorsten and Ragnar Soderberg Foundation
- Knut and Alice Wallenberg Foundation
- Swedish Cancer Society
- Wenner Gren Foundation
- Ake Wiberg Foundation
- Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa
- Swedish Society Medical Research [SSMF]
- Swedish Research Council
- Canadian Institutes of Health Research
- David and Astrid Hagelen Foundation
- Karolinska Institutet KID fund
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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.
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