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Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer

Targeted protein degradation is an attractive technology for cancer treatment due to its ability to overcome the unpredictability of the small molecule inhibitors that cause resistance mutations. In recent years, various targeted protein degradation strategies have been developed based on the ubiqui...

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Detalles Bibliográficos
Autores principales: Sakanyan, Vehary, Iradyan, Nina, Alves de Sousa, Rodolphe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526213/
https://www.ncbi.nlm.nih.gov/pubmed/37754201
http://dx.doi.org/10.3390/biotech12030057
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author Sakanyan, Vehary
Iradyan, Nina
Alves de Sousa, Rodolphe
author_facet Sakanyan, Vehary
Iradyan, Nina
Alves de Sousa, Rodolphe
author_sort Sakanyan, Vehary
collection PubMed
description Targeted protein degradation is an attractive technology for cancer treatment due to its ability to overcome the unpredictability of the small molecule inhibitors that cause resistance mutations. In recent years, various targeted protein degradation strategies have been developed based on the ubiquitin–proteasome system in the cytoplasm or the autophagy–lysosomal system during endocytosis. In this review, we describe and compare technologies for the targeted inhibition and targeted degradation of the epidermal growth factor receptor (EGFR), one of the major proteins responsible for the onset and progression of many types of cancer. In addition, we develop an alternative strategy, called alloAUTO, based on the binding of new heterocyclic compounds to an allosteric site located in close proximity to the EGFR catalytic site. These compounds cause the targeted degradation of the transmembrane receptor, simultaneously activating both systems of protein degradation in cells. Damage to the EGFR signaling pathways promotes the inactivation of Bim sensor protein phosphorylation, which leads to the disintegration of the cytoskeleton, followed by the detachment of cancer cells from the extracellular matrix, and, ultimately, to cancer cell death. This hallmark of targeted cancer cell death suggests an advantage over other targeted protein degradation strategies, namely, the fewer cancer cells that survive mean fewer chemotherapy-resistant mutants appear.
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spelling pubmed-105262132023-09-28 Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer Sakanyan, Vehary Iradyan, Nina Alves de Sousa, Rodolphe BioTech (Basel) Review Targeted protein degradation is an attractive technology for cancer treatment due to its ability to overcome the unpredictability of the small molecule inhibitors that cause resistance mutations. In recent years, various targeted protein degradation strategies have been developed based on the ubiquitin–proteasome system in the cytoplasm or the autophagy–lysosomal system during endocytosis. In this review, we describe and compare technologies for the targeted inhibition and targeted degradation of the epidermal growth factor receptor (EGFR), one of the major proteins responsible for the onset and progression of many types of cancer. In addition, we develop an alternative strategy, called alloAUTO, based on the binding of new heterocyclic compounds to an allosteric site located in close proximity to the EGFR catalytic site. These compounds cause the targeted degradation of the transmembrane receptor, simultaneously activating both systems of protein degradation in cells. Damage to the EGFR signaling pathways promotes the inactivation of Bim sensor protein phosphorylation, which leads to the disintegration of the cytoskeleton, followed by the detachment of cancer cells from the extracellular matrix, and, ultimately, to cancer cell death. This hallmark of targeted cancer cell death suggests an advantage over other targeted protein degradation strategies, namely, the fewer cancer cells that survive mean fewer chemotherapy-resistant mutants appear. MDPI 2023-09-06 /pmc/articles/PMC10526213/ /pubmed/37754201 http://dx.doi.org/10.3390/biotech12030057 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Sakanyan, Vehary
Iradyan, Nina
Alves de Sousa, Rodolphe
Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer
title Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer
title_full Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer
title_fullStr Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer
title_full_unstemmed Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer
title_short Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer
title_sort targeted strategies for degradation of key transmembrane proteins in cancer
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526213/
https://www.ncbi.nlm.nih.gov/pubmed/37754201
http://dx.doi.org/10.3390/biotech12030057
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