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Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells.

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.

SUBMITTER: Page BDG

PROVIDER: S-EPMC5772648 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells.

Page Brent D G BDG Valerie Nicholas C K NCK Wright Roni H G RHG Wallner Olov O Isaksson Rebecka R Carter Megan M Rudd Sean G SG Loseva Olga O Jemth Ann-Sofie AS Almlöf Ingrid I Font-Mateu Jofre J Llona-Minguez Sabin S Baranczewski Pawel P Jeppsson Fredrik F Homan Evert E Almqvist Helena H Axelsson Hanna H Regmi Shruti S Gustavsson Anna-Lena AL Lundbäck Thomas T Scobie Martin M Strömberg Kia K Stenmark Pål P Beato Miguel M Helleday Thomas T

Nature communications 20180117 1

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 ...[more]

PMID: 29343827

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Project description:A novel thiazole phenol conjugate, 2-aminothiazolesalicylaldehyde (receptor1) was designed and synthesized for the first time through a single step process via Schiff base condensation reaction. The formation of receptor1 was confirmed by FTIR, 13C NMR, and 1H NMR. The IR spectra confirmed the presence of the aldimine formation. It is further supported by the proton NMR, showing the disappearance of aldehyde peaks and the formation of a new imine peak. This is further corroborated by the 13C NMR. The receptor1 complexing with various metal ions were studied through fluorescence spectroscopy showed its selectivity toward Fe2+ ion following a reverse photoinduced electron transfer (PET) process compared to all other potentially competing ions. The receptor1 was applied as a sensor to sense Fe2+ ion in water samples. The detection limit for Fe2+ ion in drinking water was substantially lower (0.003 µM) than the EPA (environmental protection agency) recommendation (5.37 M). The capability of receptor1 in recovering Fe2+ ion in bore water, tap water, and drinking water was up to 99.5%. The receptor1 was also used as a chelating ligand (receptor1) in molecular docking and it was assessed as a potential inhibitor of NUDT5, a silence hormone signaling for breast cancer. The test compound (PDB: 5NWH) showed good affinity toward the target receptor1 with the binding energy of - 5.23 kcal mol-1. Furthermore, the receptor1 showed excellent reversibility property on adding EDTA solution. Due to the marvelous reversible property, a molecular-scale sequential information processing circuit is designed for the multi-task behavior such as 'Writing-Reading-Erasing-Reading' in the form of binary logic gate. The consecutive addition of Fe2+ ion and EDTA solution to receptor1 paves a way for the construction of INHIBIT logic gate. Additionally, the receptor1 showed the mimicking behavior of molecular keypad lock.Supplementary informationThe online version contains supplementary material available at 10.1007/s11696-022-02373-z.

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Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells.

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Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells.

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