Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Health and Frontiers Science Center for Disease-related Molecular Network and Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
Eur J Med Chem. 2024 Nov 15;278:116804. doi: 10.1016/j.ejmech.2024.116804. Epub 2024 Sep 2.
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.
通过合成致死（SL）靶向癌症特异性弱点是精准肿瘤学领域的一个新兴范例。基于 PARP 抑制剂的 SL 策略已显示出临床疗效。DNA 损伤反应（DDR）的进展揭示了新的 SL 基因对。除了 BRCA-PARP，新兴的 SL 靶点如 ATR、ATM、DNA-PK、CHK1、WEE1、CDK12、RAD51 和 RAD52 显示出临床潜力。已经开发出选择性和生物可用的小分子抑制剂来诱导 SL，但在效力、特异性和类药性方面的优化仍然具有挑战性。本文阐述了以能够在肿瘤细胞中特异性诱导 SL 的药物的合理设计为中心的药物化学领域的最新进展。可以预见，利用 SL 进行小分子设计的创新策略可能为靶向癌症治疗的未来开辟新的前景。
