Thursday, June 6, 2024

Covalent Degrader of the Oncogenic Transcription Factor β-Catenin

 Flor A. Gowans, Nafsika Forte, Justin Hatcher, Oscar W. Huang, Yangzhi Wang, Belen E. Altamirano Poblano, Ingrid E. Wertz, and Daniel K. Nomura

Journal of the American Chemical Society 2024

DOI: 10.1021/jacs.4c05174

β-catenin (CTNNB1) is an oncogenic transcription factor that is important in cell–cell adhesion and transcription of cell proliferation and survival genes that drive the pathogenesis of many different types of cancers. However, direct pharmacological targeting of CTNNB1 has remained challenging. Here, we have performed a screen with a library of cysteine-reactive covalent ligands to identify the monovalent degrader EN83 that depletes CTNNB1 in a ubiquitin-proteasome-dependent manner. We show that EN83 directly and covalently targets CTNNB1 three cysteines C466, C520, and C619, leading to destabilization and degradation of CTNNB1. Through structural optimization, we generate a highly potent and relatively selective destabilizing degrader that acts through the targeting of only C619 on CTNNB1. Our results show that chemoproteomic approaches can be used to covalently target and degrade challenging transcription factors like CTNNB1 through destabilization-mediated degradation.



Covalent Recruitment of NEDD4 for Targeted Protein Degradation: Rational Design of Small Molecular Degraders

Xiaoqiang He, Shihan Zeng, Yalei Wen, Tao Yang, Chaoming Huang, Yifang Li, Zhang Zhang, Ke Ding, Tongzheng Liu, Yi Tan, and Zhengqiu Li J. A...