Tubulin Resists Degradation by Cereblon-Recruiting PROTACs

Article Article scientifique Article Tubulin Resists Degradation by Cereblon-Recruiting PROTACs eng 2020-04-27 2020-04-27 author Gasic Ivana 0000-0002-4824-8174 796323 Département de biologie moléculaire et cellulaire (MOCEL) author Groendyke Brian J. 0000-0002-3860-8308 author Nowak Radosław P. 0000-0002-0605-0071 author Yuan J. Christine author Kalabathula Joann author Fischer Eric Jean Samuel 0000-0001-7337-6306 30734 author Gray Nathanael S. author Mitchison Timothy J. 1-14 1083 10.3390/cells9051083 32349222 2073-4409 PMC7290497 https://www.mdpi.com/2073-4409/9/5/1083 <p>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.</p> PROTAC Microtubule Tubulin NIGMS NIH HHS R35 GM131753 Damon Runyon Cancer Research Foundation DRG:2279-16 National Institutes of Health NCI R01CA218278 NCI NIH HHS R01 CA218278 true Cells 9 5 04d475e6-9da9-4d87-a6f7-d5e183cfc9d0 Article (Published version) Public Article-scientifique-from-unpaywall.pdf 2200910 application/pdf CC BY-4.0 bf9bfa37c7d29bacff2561f7d70475c4c9a18ef2197bc43848740fb988b8bc6d openAccess

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Tubulin Resists Degradation by Cereblon-Recruiting PROTACs	Cells			2020	66	39

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Fischer, Eric Jean Samuel