GSK5460025

GSK5460025 is an orally bioavailable small molecule inhibitor of the Werner syndrome ATP-dependent helicase (WRN), currently under clinical development by GSK. The drug is designed to exploit the principle of synthetic lethality in cancer cells characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status. In these specific genetic backgrounds, the loss of mismatch repair function leads to the accumulation of DNA secondary structures, such as TA-dinucleotide-rich cruciforms, which require WRN helicase activity for resolution and genomic stability. By inhibiting WRN, GSK5460025 induces catastrophic DNA damage, including double-strand breaks and chromosomal fragmentation, selectively in MSI-H/dMMR cells while sparing normal cells. It is primarily being investigated for the treatment of advanced or metastatic solid tumors that exhibit these biomarkers.