Chiharu Moriyama

Abstract Heterobifunctional small degrader molecules that hijack endogenous E3 ubiquitin ligases have attracted attention for the rapid and irreversible knock-down of target proteins via ubiquitination. However, the formation of appropriately oriented E3 ligase–target complexes is required for efficient ubiquitination of the target, which complicates the molecular optimization and leads to acquired drug resistance caused by the loss of E3 ligase activity and mutations at the E3–target interfaces.