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.

转染重排（rearranged during transfection, RET）突变（如G810C突变）显著限制了选择性RET抑制剂在RET驱动型癌症治疗中的临床应用。本研究以塞普替尼（selpercatinib, LOXO-292）为基础设计并评估了RET蛋白水解靶向嵌合体（proteolysis targeting chimeras, PROTACs），鉴定得到一款强效且选择性优异的RET PROTAC——RD-23。RD-23可有效抑制携带多种RET突变的BaF3细胞增殖，其半数抑制浓度（IC50）范围为2.4 nM至6.5 nM。该化合物可通过泛素-蛋白酶体系统选择性诱导RET G810C突变蛋白降解，半数降解浓度（DC50，即引发50%蛋白降解的浓度）为11.7 nM。此外，在Ba/F3-KIF5B-RET G810C异种移植小鼠模型中，RD-23展现出优于LOXO-292的口服生物利用度与抗肿瘤活性。上述研究结果表明，RD-23是一款极具开发前景的RET驱动型癌症治疗候选药物。