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 RD-23 as
a potent and selective RET PROTAC. RD-23 effectively
inhibited the proliferation of BaF3 cells with various RET mutations,
showing IC50 values of 2.4 to 6.5 nM. It selectively induced
degradation of the RETG810C mutation via the ubiquitin–proteasome
system, with a DC50 (concentration causing 50% of protein
degradation) value of 11.7 nM. Additionally, RD-23 exhibited
oral bioavailability and superior antitumor effects compared to LOXO-292
in a Ba/F3-KIF5B-RETG810C xenograft mouse model. These
results suggested that RD-23 is a promising candidate
for treating RET-driven cancers.