SHR169265

SHR169265 is a **novel small-molecule inhibitor of DNA topoisomerase I** that serves as the cytotoxic payload in the antibody-drug conjugate (ADC) SHR-A1811. It is a chemically modified derivative of exatecan, designed with a chiral cyclopropyl group at the carbonyl alpha position, which improves lipophilicity, membrane permeability, and systemic clearance. SHR169265 exhibits **potent cytotoxic effects via inhibition of DNA topoisomerase I**, leading to DNA damage and apoptotic cell death. The payload shows strong membrane permeability, contributing to pronounced bystander killing of tumor cells. It was developed to be released intracellularly after cleavage of the ADC's linker, maximizing tumor-specific cytotoxicity while minimizing systemic toxicity. SHR169265 has superior pharmacokinetic and stability profiles compared to previous payloads, with rapid systemic clearance reducing free toxin exposure. It is being developed primarily as part of the ADC SHR-A1811 for the treatment of **HER2-positive or HER2-mutant cancers**, including breast cancer, gastric cancer, colorectal cancer, and non-small cell lung cancer[1][2][3][4].