Discovery of\nan Efficacious RET PROTAC Degrader with\nEnhanced Antiproliferative Activity against Resistant Cancer Cells\nHarboring RET Solvent-Front Mutations

Rearranged during transfection (RET) kinase is a validated\ntherapeutic\ntarget for various cancers characterized by RET alterations. Although\ntwo selective RET inhibitors, selpercatinib and pralsetinib, have\nbeen approved by the FDA, acquired resistance through solvent-front\nmutations has been identified rapidly. Developing proteolysis targeting\nchimera (PROTAC) targeting RET mutations offers a promising strategy\nto combat drug resistance. Herein, we describe the design, synthesis,\nand evaluation of a series of RET PROTAC degraders. The representative\ncompound QZ2135 (<b>20</b>) effectively degraded RET kinase\nand its resistant mutants, such as V804M and G810C/R. It also exhibited\nsuperior antiproliferative activity against Ba/F3 cells stably expressing\noncogenic fusions of RET with solvent-front mutants, including G810C/R/S,\ncompared to its parental inhibitor. Notably, QZ2135 demonstrated in\nvivo antitumor efficacy in a Ba/F3-KIF5B-RET-G810C xenograft mouse\nmodel. Together, this study provides a potential alternative strategy\nfor overcoming acquired resistance to RET inhibitors mediated by solvent-front\nmutations.