Identification of [1,2,4]Triazolo[4,3-a]pyrazine PARP1 inhibitors with overcome acquired resistance activities

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors can selectively kill homologous recombination (HR) deficient cancer cells and elicit anticancer effect through a mechanism of synthetic lethality. In this study, we designed, synthesized and pharmacologically evaluated a series of [1,2,4]triazolo[4,3-a]pyrazine derivatives as a class of potent PARP1 inhibitors. Among them, compounds 17m, 19a, 19c, 19e, 19i and 19k not only displayed more potent inhibitory activities (IC₅₀s < 4.1 nM) than 9 and 1 against PARP1, but also exhibited nanomolar range of antiproliferative effects against MDA-MB-436 (BRCA1^−/−, IC₅₀s < 1.9 nM) and Capan-1 (BRCA2^−/−, IC₅₀s < 21.6 nM) cells. Notably, 19k significantly inhibited proliferation of resistant Capan-1 cells (IC₅₀s < 0.3 nM). Collectively, the newly discovered PARP1 inhibitors act as a useful pharmacological tool for investigating the mechanism of acquired resistance to PARP1 inhibitors, and may also represent promising therapeutic agents for the treatment of HR deficient cancers with the potential to overcome the acquired resistance.