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Tubulin Resists Degradation by Cereblon-Recruiting PROTACs

Dysregulation of microtubules and tubulin homeostasis has been linked to developmental disorders, neurodegenerative diseases, and cancer. In general, both microtubule-stabilizing and destabilizing agents have been powerful tools for studies of microtubule cytoskeleton and as clinical agents in oncol...

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Autores principales: Gasic, Ivana, Groendyke, Brian J., Nowak, Radosław P., Yuan, J. Christine, Kalabathula, Joann, Fischer, Eric S., Gray, Nathanael S., Mitchison, Timothy J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290497/
https://www.ncbi.nlm.nih.gov/pubmed/32349222
http://dx.doi.org/10.3390/cells9051083
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author Gasic, Ivana
Groendyke, Brian J.
Nowak, Radosław P.
Yuan, J. Christine
Kalabathula, Joann
Fischer, Eric S.
Gray, Nathanael S.
Mitchison, Timothy J.
author_facet Gasic, Ivana
Groendyke, Brian J.
Nowak, Radosław P.
Yuan, J. Christine
Kalabathula, Joann
Fischer, Eric S.
Gray, Nathanael S.
Mitchison, Timothy J.
author_sort Gasic, Ivana
collection PubMed
description Dysregulation of microtubules and tubulin homeostasis has been linked to developmental disorders, neurodegenerative diseases, and cancer. In general, both microtubule-stabilizing and destabilizing agents have been powerful tools for studies of microtubule cytoskeleton and as clinical agents in oncology. However, many cancers develop resistance to these agents, limiting their utility. We sought to address this by developing a different kind of agent: tubulin-targeted small molecule degraders. Degraders (also known as proteolysis-targeting chimeras (PROTACs)) are compounds that recruit endogenous E3 ligases to a target of interest, resulting in the target’s degradation. We developed and examined several series of α- and β-tubulin degraders, based on microtubule-destabilizing agents. Our results indicate, that although previously reported covalent tubulin binders led to tubulin degradation, in our hands, cereblon-recruiting PROTACs were not efficient. In summary, while we consider tubulin degraders to be valuable tools for studying the biology of tubulin homeostasis, it remains to be seen whether the PROTAC strategy can be applied to this target of high clinical relevance.
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spelling pubmed-72904972020-06-17 Tubulin Resists Degradation by Cereblon-Recruiting PROTACs Gasic, Ivana Groendyke, Brian J. Nowak, Radosław P. Yuan, J. Christine Kalabathula, Joann Fischer, Eric S. Gray, Nathanael S. Mitchison, Timothy J. Cells Article Dysregulation of microtubules and tubulin homeostasis has been linked to developmental disorders, neurodegenerative diseases, and cancer. In general, both microtubule-stabilizing and destabilizing agents have been powerful tools for studies of microtubule cytoskeleton and as clinical agents in oncology. However, many cancers develop resistance to these agents, limiting their utility. We sought to address this by developing a different kind of agent: tubulin-targeted small molecule degraders. Degraders (also known as proteolysis-targeting chimeras (PROTACs)) are compounds that recruit endogenous E3 ligases to a target of interest, resulting in the target’s degradation. We developed and examined several series of α- and β-tubulin degraders, based on microtubule-destabilizing agents. Our results indicate, that although previously reported covalent tubulin binders led to tubulin degradation, in our hands, cereblon-recruiting PROTACs were not efficient. In summary, while we consider tubulin degraders to be valuable tools for studying the biology of tubulin homeostasis, it remains to be seen whether the PROTAC strategy can be applied to this target of high clinical relevance. MDPI 2020-04-27 /pmc/articles/PMC7290497/ /pubmed/32349222 http://dx.doi.org/10.3390/cells9051083 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gasic, Ivana
Groendyke, Brian J.
Nowak, Radosław P.
Yuan, J. Christine
Kalabathula, Joann
Fischer, Eric S.
Gray, Nathanael S.
Mitchison, Timothy J.
Tubulin Resists Degradation by Cereblon-Recruiting PROTACs
title Tubulin Resists Degradation by Cereblon-Recruiting PROTACs
title_full Tubulin Resists Degradation by Cereblon-Recruiting PROTACs
title_fullStr Tubulin Resists Degradation by Cereblon-Recruiting PROTACs
title_full_unstemmed Tubulin Resists Degradation by Cereblon-Recruiting PROTACs
title_short Tubulin Resists Degradation by Cereblon-Recruiting PROTACs
title_sort tubulin resists degradation by cereblon-recruiting protacs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290497/
https://www.ncbi.nlm.nih.gov/pubmed/32349222
http://dx.doi.org/10.3390/cells9051083
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