Hualong Mo, Liu JieYing, Yin Ting, Cao XuXu, Su ZhengXi, Zhao Deng-Gao, Ma Yan-Yan
School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, China.
J Med Chem. 2025 Feb 13;68(3):2657-2679. doi: 10.1021/acs.jmedchem.4c01889. Epub 2025 Jan 7.
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.
转染期间重排（RET）突变，如G810C突变，严重限制了选择性RET抑制剂在治疗RET驱动癌症中的临床应用。本研究基于塞尔帕替尼（LOXO - 292）设计并评估了RET蛋白酶靶向嵌合体（PROTAC），鉴定出一种强效且选择性的RET PROTAC。其有效抑制了具有各种RET突变的BaF3细胞的增殖，IC值为2.4至6.5 nM。它通过泛素 - 蛋白酶体系统选择性诱导RET突变体的降解，DC（导致50%蛋白质降解的浓度）值为11.7 nM。此外，在Ba/F3 - KIF5B - RET异种移植小鼠模型中，与LOXO - 292相比，其表现出口服生物利用度和优异的抗肿瘤效果。这些结果表明，它是治疗RET驱动癌症的有前景的候选药物。
