Development of ADC linker payloads based on the rational design of KSP inhibitors

Abstract

The development of next-generation antibody–drug conjugates（ADCs） requires the exploration of payloads with novel mechanisms of action and the rational design of structurally diverse molecules. Through structure-activity relationship studies of cysteine derivatives with KSP inhibitory activity, the authors have discovered their potential as payloads for cancer-selective prodrug and ADC. Furthermore, enzyme-cleavable linkers were introduced to generate drug–linker constructs, and cathepsin B-mediated cleavage and structure-dependent reactivity were verified. This review outlines the design strategy and therapeutic potential of novel drug–linker systems incorporating KSP inhibitors as payloads.