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.

聚（ADP-核糖）聚合酶 1 (PARP1) 抑制剂可以选择性杀死同源重组 (HR) 缺陷的癌细胞，并通过合成致死机制引发抗癌作用。在本研究中，我们设计、合成并药理学评估了一系列作为一类有效的 PARP1 抑制剂的[1,2,4]三唑并[4,3- a ]吡嗪衍生物。其中，化合物17m、19a、19c、19e、19i和19k不仅对PARP1表现出比9和1更有效的抑制活性（IC ₅₀ s < 4.1 nM），而且对MDA-MB-表现出纳摩尔范围的抗增殖作用。 436 (BRCA1 ^−/− , IC ₅₀ s < 1.9 nM) 和 Capan-1 (BRCA2 ^−/− , IC ₅₀ s < 21.6 nM) 细胞。值得注意的是，19k显着抑制耐药 Capan-1 细胞的增殖（IC ₅₀ s < 0.3 nM）。总的来说，新发现的 PARP1 抑制剂可作为研究 PARP1 抑制剂获得性耐药机制的有用药理学工具，也可能代表治疗 HR 缺陷癌症的有前景的治疗药物，具有克服获得性耐药的潜力。