HRO761 + pembrolizumab

HRO761 + pembrolizumab is an investigational combination therapy under clinical evaluation for treating cancers characterized by high microsatellite instability (MSIhi) or mismatch repair deficiency (dMMR). HRO761 is a potent, selective, allosteric inhibitor of the **Werner syndrome RecQ helicase (WRN)** protein. By binding to the interface of the D1 and D2 helicase domains of WRN, HRO761 locks the protein in an inactive conformation, causing DNA damage and cell death selectively in MSI cells independent of p53 status[1][2][4][5]. Pembrolizumab is an approved monoclonal antibody and **programmed cell death protein 1 (PD-1) checkpoint inhibitor** used for immunotherapy of multiple cancers. The combination aims to enhance anti-tumor efficacy against MSIhi/dMMR cancers by leveraging HRO761-induced synthetic lethality along with pembrolizumab's checkpoint blockade immunotherapy[1][2][3][4][5]. HRO761 is administered orally, pembrolizumab is intravenous.