RAS-AUTOTAC

RAS-AUTOTAC is a targeted protein degrader developed using the AUTOphagy TArgeting Chimera (AUTOTAC) platform. It is a bifunctional small molecule designed to eliminate RAS proteins, which are frequently mutated oncogenes in cancers such as pancreatic, colorectal, and lung cancer. The molecule consists of a Target-Binding Ligand (TBL) that selectively recognizes the GTP-bound active form of RAS and an Autophagy-Targeting Ligand (ATL) that recruits the ZZ domain of the autophagy receptor p62 (SQSTM1). This recruitment induces p62 oligomerization, leading to the sequestration of RAS into autophagosomes and its subsequent degradation via the autophagy-lysosome pathway. Unlike mutation-specific inhibitors (e.g., G12C inhibitors), RAS-AUTOTAC demonstrates activity across multiple KRAS variants and has shown tumor growth inhibition in animal models.