Given the vulnerability of colorectal cancer (CRC) patients could not obtain a sustained benefit from chemotherapy, combination therapy is frequently employed as a treatment strategy. Targeting PARP1 blockade exhibit specific toxicity towards tumor cells with BRCA1 or BRCA2 mutations through synthetic lethality. This study focuses on developing a series of potent PROTACs targeting PARP1 in order to enhance the sensitivity of CRC cells with BRCA1 or BRCA2 mutations to chemotherapy. Compound C6, obtained based on precise structural optimization of the linker, has been shown to effectively degrade PARP1 with a DC₅₀ value of 58.14 nM. Furthermore, C6 significantly increased the cytotoxic efficacy of SN-38, an active metabolite of Irinotecan, in BRCA-mutated CRC cells, achieving a favorable combination index (CI) of 0.487. In conclusion, this research underscores the potential benefits of employing a combination therapy that utilizes PAPRP1 degrader C6 alongside Irinotecan for CRC patients harboring BRCA mutations in CRC.

中文翻译：

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发现有效的 PARP1 PROTAC 作为治疗结直肠癌的化学增敏剂


鉴于结直肠癌 （CRC） 患者的脆弱性无法从化疗中获得持续益处，联合疗法经常被用作治疗策略。靶向 PARP1 阻断通过合成致死性对具有 BRCA1 或 BRCA2 突变的肿瘤细胞表现出特异性毒性。本研究的重点是开发一系列靶向 PARP1 的强效 PROTACs，以提高具有 BRCA1 或 BRCA2 突变的 CRC 细胞对化疗的敏感性。化合物 C6 基于接头的精确结构优化获得，已被证明可有效降解 PARP1，DC₅₀ 值为 58.14 nM。此外，C6 显着增加了伊立替康的活性代谢物 SN-38 在 BRCA 突变的 CRC 细胞中的细胞毒效能，达到 0.487 的良好组合指数 （CI）。总之，这项研究强调了采用联合疗法的潜在益处，即使用 PAPRP1 降解剂 C6 和伊立替康治疗 CRC 中携带 BRCA 突变的 CRC 患者。