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

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. • Comprehensively summarize recent advances in small molecule inhibitors targeting synthetic lethality for cancer therapy. • Gathered current clinical development of inhibitors targeting synthetic lethality. • Design, SAR analyses and structural modification strategies of novel inhibitors targeting synthetic lethality. • Propose appliable suggestions for further medicinal development in synthetic lethality.