Gowans Flor A, Forte Nafsika, Hatcher Justin, Huang Oscar W, Wang Yangzhi, Altamirano Poblano Belen E, Wertz Ingrid E, Nomura Daniel K
Department of Chemistry, University of California, Berkeley, California 94720, United States.
Innovative Genomics Institute, Berkeley, California 94720, United States.
J Am Chem Soc. 2024 Jun 6. 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.
β-连环蛋白（CTNNB1）是一种致癌转录因子，在细胞间黏附以及驱动多种不同类型癌症发病机制的细胞增殖和存活基因的转录过程中发挥重要作用。然而，直接对CTNNB1进行药理学靶向作用一直具有挑战性。在此，我们使用了一个半胱氨酸反应性共价配体库进行筛选，以鉴定出以泛素-蛋白酶体依赖性方式消耗CTNNB1的单价降解剂EN83。我们表明，EN83直接且共价地靶向CTNNB1的三个半胱氨酸C466、C520和C619，导致CTNNB1的不稳定和降解。通过结构优化，我们生成了一种高效且相对选择性的去稳定化降解剂，其仅通过靶向CTNNB1上的C619起作用。我们的结果表明，化学蛋白质组学方法可用于通过去稳定化介导的降解来共价靶向和降解像CTNNB1这样具有挑战性的转录因子。
