LAUSR

F-box/WD repeat-containing protein 7 (FBXW7) is the substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. FBXW7 recognizes and binds phosphor-degrons within target proteins and capture them to SCF complex for ubiquitination. Know FBXW7 substrates include cyclin-E, DISC1, JUN, MYC, NFE2L1, NOTCH2, MCL1, RICTOR, and NOTCH1 released notch intracellular domain (NICD). FBXW7 is frequently mutated in cancer, results in loss of substrate recognition and binding. R465C is a one of the major FBXW7 mutations and is found in over 70,000 cancer patients worldwide. From a high-throughput screen, we discovered compounds that selectively bind to FBXW7 R465C mutant. PROTACs against various protein targets have been made with these mutant specific ligands. Some of these PROTACs could induce targeted protein degradation in cells carrying FBXW7 R465C mutant but not wild-type FBXW7. Targeted protein degradation with these PROTACs could represent a novel therapeutic approach against FBXW7 R465C mutant cancer. Citation Format: Zhaofu Wang, Lynette Zhang, Zhen Chang, Mengxi Zhao, Guobin Li, Fang Qin, Shichao Ma, Yunfeng Li, Zhongguo Zhang, Xinghao Wang, Ying Kong, Shidi Lou, Sheng Chen, Lanzhen Liu, Shuaijie Xu, Hailong Zhang. Discovery of cancer-specific E3 ligase ligands for targeted protein degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4962.