HRO761

HRO761 is a potent, selective, oral allosteric inhibitor of the Werner syndrome RecQ helicase (WRN). It binds at the interface of the D1 and D2 helicase domains of WRN, locking it in an inactive conformation. This inhibition leads to DNA damage and tumor cell growth inhibition selectively in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer cells in a p53-independent manner. Preclinical studies show that HRO761 induces double-stranded DNA breaks and activates the DNA damage response to promote cell death and cell cycle arrest specifically in MSI cells. The drug is being developed by Novartis for use as a targeted therapy for advanced solid tumors with MSI-H or dMMR status, including colorectal cancer. It is currently undergoing Phase 1/Ib clinical trials as both monotherapy and in combination with other agents such as pembrolizumab or irinotecan[1][2][3][4][5][6][7].