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Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets
Traditionally, small-molecule or antibody-based therapies against human diseases have been designed to inhibit the enzymatic activity or compete for the ligand binding sites of pathological target proteins. Despite its demonstrated effectiveness, such as in cancer treatment, this approach is often l...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Korean Society for Molecular and Cellular Biology
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277563/ https://www.ncbi.nlm.nih.gov/pubmed/30486612 http://dx.doi.org/10.14348/molcells.2018.0372 |
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author | Moon, Seonghyeon Lee, Byung-Hoon |
author_facet | Moon, Seonghyeon Lee, Byung-Hoon |
author_sort | Moon, Seonghyeon |
collection | PubMed |
description | Traditionally, small-molecule or antibody-based therapies against human diseases have been designed to inhibit the enzymatic activity or compete for the ligand binding sites of pathological target proteins. Despite its demonstrated effectiveness, such as in cancer treatment, this approach is often limited by recurring drug resistance. More importantly, not all molecular targets are enzymes or receptors with druggable ‘hot spots’ that can be directly occupied by active site-directed inhibitors. Recently, a promising new paradigm has been created, in which small-molecule chemicals harness the naturally occurring protein quality control machinery of the ubiquitin-proteasome system to specifically eradicate disease-causing proteins in cells. Such ‘chemically induced protein degradation’ may provide unprecedented opportunities for targeting proteins that are inherently undruggable, such as structural scaffolds and other non-enzymatic molecules, for therapeutic purposes. This review focuses on surveying recent progress in developing E3-guided proteolysis-targeting chimeras (PROTACs) and small-molecule chemical modulators of deubiquitinating enzymes upstream of or on the proteasome. |
format | Online Article Text |
id | pubmed-6277563 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Korean Society for Molecular and Cellular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-62775632018-12-13 Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets Moon, Seonghyeon Lee, Byung-Hoon Mol Cells Minireview Traditionally, small-molecule or antibody-based therapies against human diseases have been designed to inhibit the enzymatic activity or compete for the ligand binding sites of pathological target proteins. Despite its demonstrated effectiveness, such as in cancer treatment, this approach is often limited by recurring drug resistance. More importantly, not all molecular targets are enzymes or receptors with druggable ‘hot spots’ that can be directly occupied by active site-directed inhibitors. Recently, a promising new paradigm has been created, in which small-molecule chemicals harness the naturally occurring protein quality control machinery of the ubiquitin-proteasome system to specifically eradicate disease-causing proteins in cells. Such ‘chemically induced protein degradation’ may provide unprecedented opportunities for targeting proteins that are inherently undruggable, such as structural scaffolds and other non-enzymatic molecules, for therapeutic purposes. This review focuses on surveying recent progress in developing E3-guided proteolysis-targeting chimeras (PROTACs) and small-molecule chemical modulators of deubiquitinating enzymes upstream of or on the proteasome. Korean Society for Molecular and Cellular Biology 2018-11-30 2018-11-07 /pmc/articles/PMC6277563/ /pubmed/30486612 http://dx.doi.org/10.14348/molcells.2018.0372 Text en © The Korean Society for Molecular and Cellular Biology. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ |
spellingShingle | Minireview Moon, Seonghyeon Lee, Byung-Hoon Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets |
title | Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets |
title_full | Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets |
title_fullStr | Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets |
title_full_unstemmed | Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets |
title_short | Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets |
title_sort | chemically induced cellular proteolysis: an emerging therapeutic strategy for undruggable targets |
topic | Minireview |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277563/ https://www.ncbi.nlm.nih.gov/pubmed/30486612 http://dx.doi.org/10.14348/molcells.2018.0372 |
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