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Covalent Degrader of the Oncogenic Transcription Factor β-Catenin

β-catenin (CTNNB1) is an oncogenic transcription factor that is important in cell-cell adhesion and transcription of cell proliferation and survival genes that drives the pathogenesis of many different types of cancers. However, direct pharmacological targeting of CTNNB1 has remained challenging dee...

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Autores principales: Gowans, Flor A., Forte, Nafsika, Hatcher, Justin, Huang, Oscar W., Wang, Yangzhi, Poblano, Belen E. Altamirano, Wertz, Ingrid E., Nomura, Daniel K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635039/
https://www.ncbi.nlm.nih.gov/pubmed/37961622
http://dx.doi.org/10.1101/2023.10.31.565018
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author Gowans, Flor A.
Forte, Nafsika
Hatcher, Justin
Huang, Oscar W.
Wang, Yangzhi
Poblano, Belen E. Altamirano
Wertz, Ingrid E.
Nomura, Daniel K.
author_facet Gowans, Flor A.
Forte, Nafsika
Hatcher, Justin
Huang, Oscar W.
Wang, Yangzhi
Poblano, Belen E. Altamirano
Wertz, Ingrid E.
Nomura, Daniel K.
author_sort Gowans, Flor A.
collection PubMed
description β-catenin (CTNNB1) is an oncogenic transcription factor that is important in cell-cell adhesion and transcription of cell proliferation and survival genes that drives the pathogenesis of many different types of cancers. However, direct pharmacological targeting of CTNNB1 has remained challenging deeming this transcription factor as “undruggable.” Here, we have performed a screen with a library of cysteine-reactive covalent ligands to identify a monovalent degrader EN83 that depletes CTNNB1 in a ubiquitin-proteasome-dependent manner. We show that EN83 directly and covalently targets CTNNB1 through targeting four distinct cysteines within the armadillo repeat domain—C439, C466, C520, and C619—leading to a destabilization of CTNNB1. Using covalent chemoproteomic approaches, we show that EN83 directly engages CTNNB1 in cells with a moderate degree of selectivity. We further demonstrate that direct covalent targeting of three of these four cysteines--C466, C520, and C619--in cells contributes to CTNNB1 degradation in cells. We also demonstrate that EN83 can be further optimized to yield more potent CTNNB1 binders and degraders. Our results show that chemoproteomic approaches can be used to covalently target and degrade challenging transcription factors like CTNNB1 through a destabilization-mediated degradation.
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spelling pubmed-106350392023-11-13 Covalent Degrader of the Oncogenic Transcription Factor β-Catenin Gowans, Flor A. Forte, Nafsika Hatcher, Justin Huang, Oscar W. Wang, Yangzhi Poblano, Belen E. Altamirano Wertz, Ingrid E. Nomura, Daniel K. bioRxiv Article β-catenin (CTNNB1) is an oncogenic transcription factor that is important in cell-cell adhesion and transcription of cell proliferation and survival genes that drives the pathogenesis of many different types of cancers. However, direct pharmacological targeting of CTNNB1 has remained challenging deeming this transcription factor as “undruggable.” Here, we have performed a screen with a library of cysteine-reactive covalent ligands to identify a monovalent degrader EN83 that depletes CTNNB1 in a ubiquitin-proteasome-dependent manner. We show that EN83 directly and covalently targets CTNNB1 through targeting four distinct cysteines within the armadillo repeat domain—C439, C466, C520, and C619—leading to a destabilization of CTNNB1. Using covalent chemoproteomic approaches, we show that EN83 directly engages CTNNB1 in cells with a moderate degree of selectivity. We further demonstrate that direct covalent targeting of three of these four cysteines--C466, C520, and C619--in cells contributes to CTNNB1 degradation in cells. We also demonstrate that EN83 can be further optimized to yield more potent CTNNB1 binders and degraders. Our results show that chemoproteomic approaches can be used to covalently target and degrade challenging transcription factors like CTNNB1 through a destabilization-mediated degradation. Cold Spring Harbor Laboratory 2023-11-02 /pmc/articles/PMC10635039/ /pubmed/37961622 http://dx.doi.org/10.1101/2023.10.31.565018 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Gowans, Flor A.
Forte, Nafsika
Hatcher, Justin
Huang, Oscar W.
Wang, Yangzhi
Poblano, Belen E. Altamirano
Wertz, Ingrid E.
Nomura, Daniel K.
Covalent Degrader of the Oncogenic Transcription Factor β-Catenin
title Covalent Degrader of the Oncogenic Transcription Factor β-Catenin
title_full Covalent Degrader of the Oncogenic Transcription Factor β-Catenin
title_fullStr Covalent Degrader of the Oncogenic Transcription Factor β-Catenin
title_full_unstemmed Covalent Degrader of the Oncogenic Transcription Factor β-Catenin
title_short Covalent Degrader of the Oncogenic Transcription Factor β-Catenin
title_sort covalent degrader of the oncogenic transcription factor β-catenin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635039/
https://www.ncbi.nlm.nih.gov/pubmed/37961622
http://dx.doi.org/10.1101/2023.10.31.565018
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