Abstract 7211: Proteolysis targeting chimeras (PROTACs) of oncogenic RET protein

Abstract The REarranged during Transfection (RET) kinase is an oncoprotein and a therapeutic target for RET alteration-positive cancer. Two RET-selective protein tyrosine kinase inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), have been approved for treating RET-alteration-positive cancer. However, achieving a complete response with a RET kinase inhibitor remains a challenge in most patients. In cell cultures, these inhibitors increase the expression of CCDC6-RET fusion protein, which may affect their effectiveness at low concentrations. To tackle this problem, we synthesized and characterized a panel of RET PROTACs for the dual action of inhibiting RET kinase activity and degrading the oncogenic protein. A lead compound, YW-N-7, was selected based on in vitro PROTAC analyses and in vivo PK data. YW-N-7 exhibited the dual action of specifically inhibiting and degrading RET protein. Proteomic analysis identified RET as the only significantly down-regulated protein in the entire proteome by YW-N-7 compared with the RET kinase inhibitor. In the BaF3/KIF5B-RET tumor model, YW-N-7 inhibited and degraded KIF5B-RET oncoprotein in xenograft tumors in animals, and significantly inhibited tumor growth. This work illustrates the potential of developing a RET PROTAC for simultaneously inhibiting and degrading oncogenic RET kinase for cancer therapy. Citation Format: Shriya Pandey, Yafeng Wang, Xueqing Hu, Ujjwol Khatri, Tao Shen, Vivek Subbiah, Blaine H. Mooers, Ting Chao, Shaohui Wang, Huaxuan Yu, Xingmin Sun, Jianfeng Cai, Jie Wu. Proteolysis targeting chimeras (PROTACs) of oncogenic RET protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7211.