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Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges?
The classical low-molecular-weight drugs are designed to bind with high affinity to the biological targets endowed with receptor or enzymatic activity, and inhibit their function. However, there are many non-receptor or non-enzymatic disease proteins that seem undruggable using the traditional drug...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053963/ https://www.ncbi.nlm.nih.gov/pubmed/36986673 http://dx.doi.org/10.3390/pharmaceutics15030812 |
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author | Cieślak, Marcin Słowianek, Marta |
author_facet | Cieślak, Marcin Słowianek, Marta |
author_sort | Cieślak, Marcin |
collection | PubMed |
description | The classical low-molecular-weight drugs are designed to bind with high affinity to the biological targets endowed with receptor or enzymatic activity, and inhibit their function. However, there are many non-receptor or non-enzymatic disease proteins that seem undruggable using the traditional drug approach. This limitation has been overcome by PROTACs, bifunctional molecules that are able to bind the protein of interest and the E3 ubiquitin ligase complex. This interaction results in the ubiquitination of POI and subsequent proteolysis in the cellular proteasome. Out of hundreds of proteins serving as substrate receptors in E3 ubiquitin ligase complexes, current PROTACs recruit only a few of them, including CRBN, cIAP1, VHL or MDM-2. This review will focus on PROTACs recruiting CRBN E3 ubiquitin ligase and targeting various proteins involved in tumorigenesis, such as transcription factors, kinases, cytokines, enzymes, anti-apoptotic proteins and cellular receptors. The structure of several PROTACs, their chemical and pharmacokinetic properties, target affinity and biological activity in vitro and in vivo, will be discussed. We will also highlight cellular mechanisms that may affect the efficacy of PROTACs and pose a challenge for the future development of PROTACs. |
format | Online Article Text |
id | pubmed-10053963 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100539632023-03-30 Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges? Cieślak, Marcin Słowianek, Marta Pharmaceutics Review The classical low-molecular-weight drugs are designed to bind with high affinity to the biological targets endowed with receptor or enzymatic activity, and inhibit their function. However, there are many non-receptor or non-enzymatic disease proteins that seem undruggable using the traditional drug approach. This limitation has been overcome by PROTACs, bifunctional molecules that are able to bind the protein of interest and the E3 ubiquitin ligase complex. This interaction results in the ubiquitination of POI and subsequent proteolysis in the cellular proteasome. Out of hundreds of proteins serving as substrate receptors in E3 ubiquitin ligase complexes, current PROTACs recruit only a few of them, including CRBN, cIAP1, VHL or MDM-2. This review will focus on PROTACs recruiting CRBN E3 ubiquitin ligase and targeting various proteins involved in tumorigenesis, such as transcription factors, kinases, cytokines, enzymes, anti-apoptotic proteins and cellular receptors. The structure of several PROTACs, their chemical and pharmacokinetic properties, target affinity and biological activity in vitro and in vivo, will be discussed. We will also highlight cellular mechanisms that may affect the efficacy of PROTACs and pose a challenge for the future development of PROTACs. MDPI 2023-03-02 /pmc/articles/PMC10053963/ /pubmed/36986673 http://dx.doi.org/10.3390/pharmaceutics15030812 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 Cieślak, Marcin Słowianek, Marta Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges? |
title | Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges? |
title_full | Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges? |
title_fullStr | Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges? |
title_full_unstemmed | Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges? |
title_short | Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges? |
title_sort | cereblon-recruiting protacs: will new drugs have to face old challenges? |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053963/ https://www.ncbi.nlm.nih.gov/pubmed/36986673 http://dx.doi.org/10.3390/pharmaceutics15030812 |
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