Diseño, síntesis y evaluación de la actividad de degradación de la proteína RET basada en técnicas PROTAC e HyTTD

Point mutations and fusions in the Rearranged during Transfection (RET) proto-oncogene are established drivers in diverse malignancies. Although selective RET inhibitors such as selpercatinib and pralsetinib have been clinically approved, the emergence of resistance mutations limits their durable efficacy, underscoring the need for novel therapeutic modalities. Targeted protein degradation (TPD), which harnesses the endogenous ubiquitin-proteasome system to induce protein degradation, provides a promising strategy to overcome resistance to traditional small-molecule inhibitors. In this study, we systematically evaluated two distinct TPD approaches, proteolysis-targeting chimeras (PROTACs) and hydrophobic tag tethering degraders (HyTTDs). We report the design and synthesis of the first RET-targeting HyTTD, compound B2, which achieves 91.4% degradation of CCDC6-RET fusion protein in TPC-1 cells at 10 μM within 48 h. These results not only validate hydrophobic tag tethering as a feasible strategy for RET degradation but also propose a new therapeutic direction for RET-driven cancers.