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Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications

Posttranslational modifications (PTMs) play an important role in cell signaling and they are often deregulated in disease. This review addresses recent advances in the development of heterobifunctional small molecules that enable targeting or hijacking PTMs. This emerging field is spearheaded by pro...

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Autor principal: Heitel, Pascal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9867477/
https://www.ncbi.nlm.nih.gov/pubmed/36677746
http://dx.doi.org/10.3390/molecules28020690
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author Heitel, Pascal
author_facet Heitel, Pascal
author_sort Heitel, Pascal
collection PubMed
description Posttranslational modifications (PTMs) play an important role in cell signaling and they are often deregulated in disease. This review addresses recent advances in the development of heterobifunctional small molecules that enable targeting or hijacking PTMs. This emerging field is spearheaded by proteolysis-targeting chimeras (PROTACs), that induce ubiquitination of their targets and, thus, tag them for degradation by the proteasome. Within the last decade, several improvements have been made to enhance spatiotemporal control of PROTAC-induced degradation as well as cell permeability. Inspired by the success story of PROTACs, additional concepts based on chimeric small molecules have emerged such as phosphatase-recruiting chimeras (PhoRCs). Herein, an overview of strategies causing (de-)phosphorylation, deubiquitination as well as acetylation is provided, and the opportunities and challenges of heterobifunctional molecules for drug discovery are highlighted. Although significant progress has been achieved, a plethora of PTMs have not yet been covered and PTM-inducing chimeras will be helpful tools for chemical biology and could even find application in pharmacotherapy.
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spelling pubmed-98674772023-01-22 Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications Heitel, Pascal Molecules Review Posttranslational modifications (PTMs) play an important role in cell signaling and they are often deregulated in disease. This review addresses recent advances in the development of heterobifunctional small molecules that enable targeting or hijacking PTMs. This emerging field is spearheaded by proteolysis-targeting chimeras (PROTACs), that induce ubiquitination of their targets and, thus, tag them for degradation by the proteasome. Within the last decade, several improvements have been made to enhance spatiotemporal control of PROTAC-induced degradation as well as cell permeability. Inspired by the success story of PROTACs, additional concepts based on chimeric small molecules have emerged such as phosphatase-recruiting chimeras (PhoRCs). Herein, an overview of strategies causing (de-)phosphorylation, deubiquitination as well as acetylation is provided, and the opportunities and challenges of heterobifunctional molecules for drug discovery are highlighted. Although significant progress has been achieved, a plethora of PTMs have not yet been covered and PTM-inducing chimeras will be helpful tools for chemical biology and could even find application in pharmacotherapy. MDPI 2023-01-10 /pmc/articles/PMC9867477/ /pubmed/36677746 http://dx.doi.org/10.3390/molecules28020690 Text en © 2023 by the author. 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
Heitel, Pascal
Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications
title Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications
title_full Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications
title_fullStr Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications
title_full_unstemmed Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications
title_short Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications
title_sort emerging tacnology: heterobifunctional small molecule inducers of targeted posttranslational protein modifications
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9867477/
https://www.ncbi.nlm.nih.gov/pubmed/36677746
http://dx.doi.org/10.3390/molecules28020690
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