TH5427 hydrochloride

TH5427 hydrochloride is a NUDT5 inhibitor with a human target IC₅₀ of 29 nM, ~690-fold selectivity over MTH1 in vitro, and selective functional inhibition over other NUDIX hydrolases including NUDT9.TH5427 hydrochloride binds to the active site of NUDT5, blocking enzymatic activity related to ADP-ribose metabolism and PAR-derived ATP synthesis.TH5427 hydrochloride blocks progestin-dependent nuclear ATP synthesis, impairs progestin-induced chromatin remodeling, inhibits histone H1 displacement, disrupts progestin-dependent gene regulation, and abrogates progestin-dependent proliferation in breast cancer cells.TH5427 hydrochloride functions as a versatile probe to study nuclear ATP dynamics and ADP-ribose-related metabolism in cells.TH5427 hydrochloride engages NUDT5 at physiological temperatures, as demonstrated by Drug Affinity Responsive Target Stability (DARTS) assay.TH5427 hydrochloride stabilizes NUDT5 against thermal denaturation in cell lysates and intact cells, as shown by cellular thermal shift assay (CETSA).TH5427 hydrochloride functionally inhibits NUDT5 activity, leading to downstream effects on oxidative DNA damage and DNA replication in triple-negative breast cancer (TNBC) cells.TH5427 hydrochloride suppresses proliferation of TNBC cells without inducing cell death or apoptosis, slows DNA replication in TNBC cells, promotes accumulation of oxidative DNA lesions, and triggers DNA damage response in TNBC cells.TH5427 hydrochloride suppresses growth of TNBC cells in vitro, inhibits growth of TNBC xenograft tumors in nude mice in vivo, and shows greater potency against TNBC cell lines compared to ER-positive and normal-like breast cell lines.TH5427 hydrochloride can be used for the research of breast cancer and triple-negative breast cancer.

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