WRN inhibitor HRO761

An orally bioavailable selective and allosteric inhibitor of the Werner syndrome ATP-dependent helicase (WRN), with potential antineoplastic activity. Upon oral administration, WRN inhibitor HRO761 allosterically binds at the interface of the D1 and D2 helicase domains of WRN, thereby locking WRN in an inactive conformation. This induces double-stranded DNA breaks and activates the DNA damage response (DDR) to induce WRN degradation. This promotes cell cycle arrest and cell death in, and inhibits the growth of susceptible tumor cells, such as ones with high microsatellite instability (MSI-H). WRN, a multifunctional enzyme with both helicase and exonuclease activities, plays a key role in DNA replication and repair. It is overexpressed in a variety of cancer cells.