The emergence of resistance to PARP1 inhibitors poses a current therapeutic challenge, necessitating the development of novel strategies to overcome this obstacle. The present study describes the design and synthesis of a series of small molecules that target both PARP1 and c-Met. Among them, compound 16 is identified as a highly potent dual inhibitor, exhibiting excellent inhibitory activities against PARP1 (IC₅₀ = 3.3 nM) and c-Met (IC₅₀ = 32.2 nM), as well as demonstrating good antiproliferative effects on HR-proficient cancer cell lines and those resistant to PARP1 inhibitors. Importantly, compound 16 demonstrates superior antitumor potency compared to the PARP1 inhibitor Olaparib and the c-Met inhibitor Crizotinib, either alone or in combination, in MDA-MB-231 and HCT116OR xenograft models. These findings highlight the potential of PARP1/c-Met dual inhibitors for expanding the indications of PARP1 inhibitors and overcoming tumor cells’ resistance to them.

中文翻译：

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合理设计 PARP1/c-Met 双抑制剂以克服 c-Met 过表达引起的 PARP1 抑制剂耐药性

PARP1 抑制剂耐药性的出现给当前的治疗带来了挑战，需要开发新的策略来克服这一障碍。本研究描述了一系列针对 PARP1 和 c-Met 的小分子的设计和合成。其中，化合物16被认为是一种高效的双重抑制剂，对PARP1（IC ₅₀ = 3.3 nM）和c-Met（IC ₅₀ = 32.2 nM）表现出优异的抑制活性，并对HR熟练的细胞表现出良好的抗增殖作用。癌细胞系和对 PARP1 抑制剂具有抗性的细胞系。重要的是，在 MDA-MB-231 和 HCT116OR 异种移植模型中，与 PARP1 抑制剂 Olaparib 和 c-Met 抑制剂 Crizotinib（单独或组合）相比，化合物16表现出更优异的抗肿瘤效力。这些发现凸显了 PARP1/c-Met 双抑制剂在扩大 PARP1 抑制剂适应症和克服肿瘤细胞对其耐药性方面的潜力。