Targeted degradation of KRAS using the AUTOTAC platform

RAS is one of the most frequently mutated oncogenes in human cancers, with KRAS mutations being particularly prevalent: accounting for approximately 95% of pancreatic cancers, 45% of colorectal cancers, and 20% of lung cancers. Due to its lack of deep pockets for ligand binding, RAS has long been considered an “undruggable target,” despite more than three decades of intensive drug discovery efforts. Although small-molecule inhibitors targeting KRAS G12C have recently been developed, their therapeutic effect is limited to this specific mutation, underscoring the need for strategies capable of targeting a broader range of KRAS variants.AUTOphagy TArgeting Chimera (AUTOTAC) is a recently developed targeted protein degradation platform that harnesses the autophagy pathway to eliminate pathological proteins. In this study, we applied AUTOTAC technology to RAS, generating RAS-AUTOTAC, a bifunctional small molecule composed of a Target-Binding Ligand (TBL) linked to an Autophagy-Targeting Ligand (ATL). Upon binding to RAS via the TBL, the ATL component recruits the ZZ domain of p62, inducing p62 oligomerization and initiating autophagic degradation. During this process, RAS becomes biologically inactivated and sequestered into autophagosomes. RAS-AUTOTAC suppresses downstream oncogenic signaling through p62 oligomerization and subsequent autophagic degradation. Importantly, RAS-AUTOTAC selectively recognizes the GTP-bound active form of RAS and effectively suppresses RAS signaling across multiple KRAS variants. Moreover, RAS-AUTOTAC demonstrated tumor growth inhibition in animal models, supporting its functional activity in vivo .Collectively, our results provide a mechanistic basis for applying AUTOTAC to RAS-driven cancers.