TH1760 (TH 1760) is a first-in-class, potent, selective, cell-active NUDT15 inhibitor with IC50 of 25 nM.
TH1760 displays no significant interaction and/or inhibition againstother human NUDIX proteins (MTH1, NUDT2, NUDT5, NUDT9, NUDT12, NUDT14, NUDT18 and NUDT22) and nucleotide pyrophosphatases (dCTPase, dUTPase and ITPase).
TH1760 sensitized cells to thiopurine in a NUDT15-dependent manner, through promoting intracellular accumulation and incorporation of 6-thio-dGTP.
At the tested concentration of 10 μM, TH1760 effectively engaged intracellular NUDT15 and further strongly potentiated its substrate thiopurines metabolites, without demonstrating apparent off-target toxicity.
TH1760 is a valuable tool to decipher the potential of NUDT15 inhibition in overcoming emerging resistance during thiopurine therapy.
