Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer Cells Harboring RET Solvent-Front Mutations

Rearranged during transfection (RET) kinase is a validated
therapeutic
target for various cancers characterized by RET alterations. Although
two selective RET inhibitors, selpercatinib and pralsetinib, have
been approved by the FDA, acquired resistance through solvent-front
mutations has been identified rapidly. Developing proteolysis targeting
chimera (PROTAC) targeting RET mutations offers a promising strategy
to combat drug resistance. Herein, we describe the design, synthesis,
and evaluation of a series of RET PROTAC degraders. The representative
compound QZ2135 (20) effectively degraded RET kinase
and its resistant mutants, such as V804M and G810C/R. It also exhibited
superior antiproliferative activity against Ba/F3 cells stably expressing
oncogenic fusions of RET with solvent-front mutants, including G810C/R/S,
compared to its parental inhibitor. Notably, QZ2135 demonstrated in
vivo antitumor efficacy in a Ba/F3-KIF5B-RET-G810C xenograft mouse
model. Together, this study provides a potential alternative strategy
for overcoming acquired resistance to RET inhibitors mediated by solvent-front
mutations.