Targeting WRN helicase in MSI-H tumors: Synthetic lethality, small molecule discovery, and therapeutic perspectives

Synthetic lethality strategies targeting the DNA damage response have revolutionized cancer therapy. However, established agents like PARP inhibitors face limitations regarding resistance mechanisms and narrow therapeutic indices. Recent functional genomics have identified the Werner syndrome RecQ helicase (WRN) as a critical synthetic lethal vulnerability specifically in microsatellite instability-high (MSI-H) tumors. Pharmacological inhibition of WRN precipitates replication fork collapse and double-strand breaks, validating it as a promising therapeutic target. Despite this potential, the clinical translation of WRN inhibitors is still in its nascent stages. This review provides a comprehensive overview of the structural biology of WRN and the mechanistic basis of its selectivity in MSI-H cancers. We critically analyze the medicinal chemistry campaigns leading to the discovery of current covalent and non-covalent chemotypes, with a focus on structure-activity relationship optimization and binding modes. Furthermore, emerging modalities and key obstacles to clinical development are discussed. By integrating recent advances, this article aims to provide a conceptual framework and strategic insights for the continued development of next-generation WRN therapeutics.