Targeting WRN helicase: Discovery and development of its selective inhibitors

Werner syndrome protein (WRN) is a crucial helicase associated with the genetic disorder Werner syndrome. In recent years, the discovery of a synthetic lethal relationship between WRN helicase and microsatellite instability (MSI) has positioned WRN as a promising target for cancer therapy. This review provides an overview of the structure and function of WRN, as well as the molecular mechanisms underlying the WRN dependency of MSI tumors. Besides, a summary of the current landscape of WRN inhibitors is presented, including both covalent and non-covalent compounds, along with an introduction of proof-of-concept studies on WRN-targeting proteolysis-targeting chimeras (PROTACs). Key considerations for the effective screening and development of WRN inhibitors are also discussed, aiming to provide a timely and updated overview on the strategies for targeting WRN.