GSK4418959A

GSK4418959A is an orally bioavailable small molecule inhibitor of Tyrosyl-DNA phosphodiesterase 1 (TDP1), currently under development by GSK for the treatment of advanced solid tumors. TDP1 is a specialized DNA repair enzyme responsible for resolving stalled topoisomerase I (TOP1)-DNA covalent complexes (TOP1cc) that can be induced by chemotherapy agents like irinotecan or by endogenous DNA damage. By inhibiting TDP1, GSK4418959A prevents the repair of these lethal DNA lesions, thereby sensitizing tumor cells to the cytotoxic effects of TOP1 poisons. The drug is being investigated in clinical trials as both a monotherapy and in combination with other agents, with a particular focus on patients with colorectal cancer, endometrial cancer, and tumors characterized by mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H).