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.

中文翻译：

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靶向的NUDT5抑制剂可阻断乳腺癌细胞中的激素信号传导。

随着底物网络的多样化，NUDIX水解酶已成为核苷酸代谢酶的关键家族。NUDT5（也称为NUDIX5）与ADP-核糖和8-氧代鸟嘌呤的代谢有关，最近被确定为乳腺癌细胞中激素依赖性基因调控和增殖的变阻器。在这里，我们进一步阐明了已知NUDT5底物的生理相关性，并强调了NUDT5在乳腺癌细胞的基因调控和增殖中的生物学需求。我们确认NUDT5参与ADP-核糖代谢，并解除了与氧化核苷酸卫生设施的关系。此外，我们确定了有效的NUDT5抑制剂，这些抑制剂经优化可促进CETSA促进最大的NUDT5细胞靶标参与。铅化合物TH5427可阻止孕激素依赖性 PAR衍生的核ATP合成以及随后的染色质重塑，基因调控和乳腺癌细胞增殖。我们在此提出TH5427作为一种有前途的靶向抑制剂，可用于进一步研究NUDT5活性和ADP-核糖代谢。