Covalent Degrader of the Oncogenic Transcription Factor β-Catenin.

Autor: Gowans FA; Department of Chemistry, University of California, Berkeley, California 94720, United States.; Innovative Genomics Institute, Berkeley, California 94720, United States., Forte N; Department of Chemistry, University of California, Berkeley, California 94720, United States.; Innovative Genomics Institute, Berkeley, California 94720, United States., Hatcher J; Department of Chemistry, University of California, Berkeley, California 94720, United States.; Innovative Genomics Institute, Berkeley, California 94720, United States., Huang OW; Bristol Myers Squibb, San Francisco, California 94158, United States., Wang Y; Department of Chemistry, University of California, Berkeley, California 94720, United States.; Innovative Genomics Institute, Berkeley, California 94720, United States., Altamirano Poblano BE; Department of Chemistry, University of California, Berkeley, California 94720, United States.; Innovative Genomics Institute, Berkeley, California 94720, United States., Wertz IE; Bristol Myers Squibb, San Francisco, California 94158, United States., Nomura DK; Department of Chemistry, University of California, Berkeley, California 94720, United States.; Innovative Genomics Institute, Berkeley, California 94720, United States.; Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, United States.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2024 Jun 06. Date of Electronic Publication: 2024 Jun 06.
DOI: 10.1021/jacs.4c05174
Abstrakt: 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.
Databáze: MEDLINE
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