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Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

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.

 

Comments:

The passage you provided discusses the role of NUDIX hydrolases, specifically NUDT5, in nucleotide metabolism and its implications in hormone-dependent gene regulation and proliferation in breast cancer cells. The researchers aimed to understand the physiological relevance of NUDT5 substrates and its involvement in ADP-ribose metabolism, separate from oxidized nucleotide sanitation. They also identified potent NUDT5 inhibitors, with TH5427 being highlighted as a lead compound. TH5427 was found to block progestin-dependent, PAR-derived nuclear ATP synthesis, leading to the inhibition of chromatin remodeling, gene regulation, and proliferation in breast cancer cells.

In summary, this research sheds light on the significance of NUDT5 in breast cancer cell biology, highlighting its role in ADP-ribose metabolism and gene regulation. The discovery of TH5427 as an inhibitor provides a promising avenue for further studying NUDT5 activity and its involvement in ADP-ribose metabolism in the context of breast cancer.

Related Products

Cat.No. Product Name Information
E2849 TH5427 TH5427 is a potent and cell-active NUDT5 (also called NUDIX5) inhibitor that can be used to further understand the role of NUDT5 in biological systems.

Related Targets

NUDIX