Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15–54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC₅₀ = 1.3 nM), V-C8 cells (IC₅₀ = 0.003 nM), Capan-1 cells (IC₅₀ = 7.1 nM) and MDA-MB-436 cells (IC₅₀ = 0.2 nM). Compound 47 had more potent PARP1-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors.

聚（ADP-核糖）聚合酶1（PARP1）在多种癌症（尤其是乳腺癌和卵巢癌）中过表达，缺乏乳腺癌基因1/2（BRCA1 / 2）的肿瘤细胞系对PARP1抑制高度敏感。在这项研究中，借助于分子对接，我们确定了一系列新的2,3-二氟苯基连接子类似物（15 – 54），其是从olaparib（1）衍生而来的PARP1抑制剂。铅优化导致鉴定出47个，对PARP1酶（IC ₅₀  = 1.3 nM），V-C8细胞（IC ₅₀  = 0.003 nM），Capan-1细胞（IC ₅₀）表现出高选择性和高效力 = 7.1 nM）和MDA-MB-436细胞（IC ₅₀  = 0.2 nM）。化合物47具有比1更有效的PARP1-DNA捕获和双链断裂（DSBs）诱导活性，并诱导G2 / M阻滞和caspase依赖性凋亡。在BRCA1突变的异种移植模型中，化合物47（50 mg / kg，94.2％）对肿瘤生长的抑制作用优于1（100 mg / kg，65.0％），并显着抑制了肿瘤生长（40 mg / kg，48.1） ％）在BRCA2突变的异种移植模型中，对小鼠的体重没有负面影响。总体而言，这些数据表明47可能是治疗癌症（尤其是BRCA缺陷型肿瘤）的优秀候选药物。