Discovery of a Selective and Orally Bioavailable RET Degrader with Effectiveness in Various Mutations

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Rearranged during transfection (RET) mutations, like G810C, limit current RET inhibitor efficacy in RET-driven cancers.
• Developing novel therapeutic strategies is crucial to overcome resistance mechanisms and improve treatment outcomes.

Purpose of the Study:

• To design and evaluate novel RET proteolysis targeting chimeras (PROTACs) to overcome RET inhibitor resistance.
• To identify a potent and selective RET PROTAC capable of degrading mutated RET proteins.

Main Methods:

• Designed and synthesized RET PROTACs based on the selpercatinib (LOXO-292) scaffold.
• Assessed antiproliferative activity and RET protein degradation in cell-based assays.
• Evaluated oral bioavailability and in vivo efficacy in a xenograft mouse model.

Main Results:

• Identified RD-23 as a potent and selective RET PROTAC with nanomolar IC50 values against various RET mutations.
• RD-23 selectively induced degradation of the RET^G810C mutation via the ubiquitin-proteasome system (DC50 = 11.7 nM).
• RD-23 demonstrated oral bioavailability and superior antitumor efficacy compared to LOXO-292 in vivo.

Conclusions:

• RD-23 is a potent RET PROTAC that effectively degrades mutated RET proteins, including the G810C variant.
• RD-23 exhibits promising therapeutic potential for treating RET-driven cancers, including those resistant to conventional inhibitors.