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Recent advances in targeted protein degraders as potential therapeutic agents
Targeted protein degradation (TPD) technology has gradually become widespread in the past 20 years, which greatly boosts the development of disease treatment. Contrary to small inhibitors that act on protein kinases, transcription factors, ion channels, and other targets they can bind to, targeted p...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9930057/ https://www.ncbi.nlm.nih.gov/pubmed/36790583 http://dx.doi.org/10.1007/s11030-023-10606-w |
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author | Yang, Na Kong, Bo Zhu, Zhaohong Huang, Fei Zhang, Liliang Lu, Tao Chen, Yadong Zhang, Yanmin Jiang, Yulei |
author_facet | Yang, Na Kong, Bo Zhu, Zhaohong Huang, Fei Zhang, Liliang Lu, Tao Chen, Yadong Zhang, Yanmin Jiang, Yulei |
author_sort | Yang, Na |
collection | PubMed |
description | Targeted protein degradation (TPD) technology has gradually become widespread in the past 20 years, which greatly boosts the development of disease treatment. Contrary to small inhibitors that act on protein kinases, transcription factors, ion channels, and other targets they can bind to, targeted protein degraders could target “undruggable targets” and overcome drug resistance through ubiquitin–proteasome pathway (UPP) and lysosome pathway. Nowadays, some bivalent degraders such as proteolysis-targeting chimeras (PROTACs) have aroused great interest in drug discovery, and some of them have successfully advanced into clinical trials. In this review, to better understand the mechanism of degraders, we elucidate the targeted protein degraders according to their action process, relying on the ubiquitin–proteasome system or lysosome pathway. Then, we briefly summarize the study of PROTACs employing different E3 ligases. Subsequently, the effect of protein of interest (POI) ligands, linker, and E3 ligands on PROTAC degradation activity is also discussed in detail. Other novel technologies based on UPP and lysosome pathway have been discussed in this paper such as in-cell click-formed proteolysis-targeting chimeras (CLIPTACs), molecular glues, Antibody-PROTACs (Ab-PROTACs), autophagy-targeting chimeras, and lysosome-targeting chimeras. Based on the introduction of these degradation technologies, we can clearly understand the action process and degradation mechanism of these approaches. From this perspective, it will be convenient to obtain the development status of these drugs, choose appropriate degradation methods to achieve better disease treatment and provide basis for future research and simultaneously distinguish the direction of future research efforts. GRAPHICAL ABSTRACT: Protein is degraded by proteasome pathway and lysosome pathway. [Image: see text] |
format | Online Article Text |
id | pubmed-9930057 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-99300572023-02-15 Recent advances in targeted protein degraders as potential therapeutic agents Yang, Na Kong, Bo Zhu, Zhaohong Huang, Fei Zhang, Liliang Lu, Tao Chen, Yadong Zhang, Yanmin Jiang, Yulei Mol Divers Comprehensive Review Targeted protein degradation (TPD) technology has gradually become widespread in the past 20 years, which greatly boosts the development of disease treatment. Contrary to small inhibitors that act on protein kinases, transcription factors, ion channels, and other targets they can bind to, targeted protein degraders could target “undruggable targets” and overcome drug resistance through ubiquitin–proteasome pathway (UPP) and lysosome pathway. Nowadays, some bivalent degraders such as proteolysis-targeting chimeras (PROTACs) have aroused great interest in drug discovery, and some of them have successfully advanced into clinical trials. In this review, to better understand the mechanism of degraders, we elucidate the targeted protein degraders according to their action process, relying on the ubiquitin–proteasome system or lysosome pathway. Then, we briefly summarize the study of PROTACs employing different E3 ligases. Subsequently, the effect of protein of interest (POI) ligands, linker, and E3 ligands on PROTAC degradation activity is also discussed in detail. Other novel technologies based on UPP and lysosome pathway have been discussed in this paper such as in-cell click-formed proteolysis-targeting chimeras (CLIPTACs), molecular glues, Antibody-PROTACs (Ab-PROTACs), autophagy-targeting chimeras, and lysosome-targeting chimeras. Based on the introduction of these degradation technologies, we can clearly understand the action process and degradation mechanism of these approaches. From this perspective, it will be convenient to obtain the development status of these drugs, choose appropriate degradation methods to achieve better disease treatment and provide basis for future research and simultaneously distinguish the direction of future research efforts. GRAPHICAL ABSTRACT: Protein is degraded by proteasome pathway and lysosome pathway. [Image: see text] Springer International Publishing 2023-02-15 /pmc/articles/PMC9930057/ /pubmed/36790583 http://dx.doi.org/10.1007/s11030-023-10606-w Text en © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Comprehensive Review Yang, Na Kong, Bo Zhu, Zhaohong Huang, Fei Zhang, Liliang Lu, Tao Chen, Yadong Zhang, Yanmin Jiang, Yulei Recent advances in targeted protein degraders as potential therapeutic agents |
title | Recent advances in targeted protein degraders as potential therapeutic agents |
title_full | Recent advances in targeted protein degraders as potential therapeutic agents |
title_fullStr | Recent advances in targeted protein degraders as potential therapeutic agents |
title_full_unstemmed | Recent advances in targeted protein degraders as potential therapeutic agents |
title_short | Recent advances in targeted protein degraders as potential therapeutic agents |
title_sort | recent advances in targeted protein degraders as potential therapeutic agents |
topic | Comprehensive Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9930057/ https://www.ncbi.nlm.nih.gov/pubmed/36790583 http://dx.doi.org/10.1007/s11030-023-10606-w |
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