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An update on small molecule compounds targeting synthetic lethality for cancer therapy

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机构： [1]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. [2]Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.

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关键词： Synthetie lethality small molecules cancer therapy drug discovery

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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.Copyright © 2024 Elsevier Masson SAS. All rights reserved.

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大类 | 2 区

医学

小类 | 1 区药物化学

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第一作者机构： [1]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.

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