The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC₅₀ of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC₅₀ of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway.

核蛋白聚（ADP-核糖）聚合酶-1/2（PARP-1 / 2）参与被内源或外源过程破坏的DNA修复。在过去十年中，PARP-1 / 2抑制剂已被证明对DNA修复缺陷型肿瘤有效。我们已经开发了一系列4,5,6,7-四氢噻吩并吡啶-2-基苯并咪唑羧酰胺作为新型有效的PARP-1 / 2抑制剂。由该系列得到的最好的化合物是化合物27，该化合物具有出色的PARP-1和PARP-2抑制活性，IC _50分别为18 nM和42 nM。此外，它可以用CC ₅₀选择性杀死BRCA2缺陷的V-C8细胞920 nM。在MDA-MB-436（BRCA-1突变体）异种移植模型中，该化合物具有良好的耐受性，并显示出单药活性。基于以上结果，化合物27已被选为靶向PARP-1 / 2的首要候选药物，其临床前表征也在进行中。