HRO761 + irinotecan

**HRO761 + irinotecan** is an investigational combination therapy consisting of HRO761, an oral, clinical-stage small molecule inhibitor of the Werner syndrome RecQ helicase (WRN), and irinotecan, an approved cytotoxic chemotherapeutic that inhibits topoisomerase I. HRO761 selectively and potently binds and allosterically inactivates WRN by engaging the interface of the D1 and D2 helicase domains, resulting in DNA damage, cell cycle arrest, and cell death specifically in microsatellite instability-high (MSI-hi) or mismatch repair-deficient (dMMR) cancer cells, independently of p53 status[1][3][5]. Irinotecan acts through inhibition of topoisomerase I, causing DNA strand breaks during replication. Preclinical and ongoing clinical data indicate that combining HRO761 with irinotecan leads to synergistic potentiation of DNA damage, enhanced anti-proliferative effects, and promoted complete tumor regression in MSI colorectal and other MSI solid tumor models with good tolerability[1][2][3][4][5][7].