Targeting cancer-specific vulnerabilities through synthetic lethality (SL) is an emerging paradigm in precision oncology. A SL strategy based on PARP inhibitors has demonstrated clinical efficacy. Advances in DNA damage response (DDR) uncover novel SL gene pairs. Beyond BRCA-PARP, emerging SL targets like ATR, ATM, DNA-PK, CHK1, WEE1, CDK12, RAD51, and RAD52 show clinical promise. Selective and bioavailable small molecule inhibitors have been developed to induce SL, but optimization for potency, specificity, and drug-like properties remains challenging. This article illuminated recent progress in the field of medicinal chemistry centered on the rational design of agents capable of eliciting SL specifically in neoplastic cells. It is envisioned that innovative strategies harnessing SL for small molecule design may unlock novel prospects for targeted cancer therapeutics going forward.

中文翻译：

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针对癌症治疗的合成致死作用的小分子化合物的最新进展


通过合成致死（SL）来针对癌症特定的脆弱性是精准肿瘤学的一个新兴范例。基于 PARP 抑制剂的 SL 策略已证明临床疗效。 DNA 损伤反应 (DDR) 的进展揭示了新的 SL 基因对。除了 BRCA-PARP 之外，ATR、ATM、DNA-PK、CHK1、WEE1、CDK12、RAD51 和 RAD52 等新兴 SL 靶点也显示出临床前景。选择性和生物可利用的小分子抑制剂已被开发用于诱导 SL，但效力、特异性和类药物特性的优化仍然具有挑战性。本文阐述了药物化学领域的最新进展，重点是合理设计能够在肿瘤细胞中特异性引发 SL 的药物。预计利用 SL 进行小分子设计的创新策略可能会为靶向癌症治疗开辟新的前景。