First-in-class MTH1 inhibitor (IC50 value 5.0 nM) that selectively and effectively kills U2OS and other cancer cell lines, with considerably less toxicity towards several primary or immortalized cells. Similar to TH 287, TH 588 shows no relevant inhibitory effect for any of the other tested nudix hydrolase protein family members MTH2, NUDT5, NUDT12, NUDT14, and NUDT16, nor for other proteins with known nucleoside triphosphate pyrophosphatase activity (dCTPase, dUTPase and ITPA).
Replacement of the methyl group by a cyclopropyl substituent in TH 588 (compared to TH 287, Axon 2271) improved metabolic stability both in vitro and in vivo, while maintaining MTH1 potency.