Targeting MMR-deficient colorectal cancer with a potent small molecule UNI110.

Abstract

Mismatch repair (MMR) deficiency is a hallmark of microsatellite instability (MSI) in hereditary non-polyposis colorectal cancer, Lynch syndrome, contributing to resistance against conventional chemotherapy and posing a significant therapeutic challenge. In this study, we introduce UNI110, a novel small molecule derived from Baicalein, engineered for enhanced selectivity against MMR-deficient cancer cells. UNI110 exhibits a remarkable sevenfold increase in potency over Baicalein, demonstrating significantly lower IC50 values and heightened cytotoxic effects in MMR-deficient cell lines. Mechanistically, UNI110 selectively induces DNA damage in MMR-deficient cancer cells, ultimately resulting in cell death. Furthermore, UNI110 disrupts homologous recombination (HR) repair by inhibiting the MSH2-MSH3 complex, specifically blocking the interaction between MSH2 and EXO1, thereby impairing long-range end resection during double-strand break (DSB) repair. These findings establish UNI110 as a promising lead compound for the targeted treatment of MMR-deficient colorectal cancers, offering a potential breakthrough in overcoming chemotherapy resistance and improving patient outcomes.