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

The rearranged during transfection (RET) mutation such as the G810C mutation has significantly restricted the clinical application of selective RET inhibitors in the treatment of RET-driven cancers. This study designed and evaluated RET proteolysis targeting chimeras (PROTACs) based on selpercatinib (LOXO-292), identifying as a potent and selective RET PROTAC. effectively inhibited the proliferation of BaF3 cells with various RET mutations, showing IC values of 2.4 to 6.5 nM. It selectively induced degradation of the RET mutation via the ubiquitin-proteasome system, with a DC (concentration causing 50% of protein degradation) value of 11.7 nM. Additionally, exhibited oral bioavailability and superior antitumor effects compared to LOXO-292 in a Ba/F3-KIF5B-RET xenograft mouse model. These results suggested that is a promising candidate for treating RET-driven cancers.