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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Tubulin Resists Degradation by Cereblon-Recruiting PROTACs
Ivana Gasic1, Brian J Groendyke2,3, Radosław P Nowak2,3
1Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
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.
Insights
Researchers explored tubulin degraders, a novel approach to target cancer, but found cereblon-recruiting proteolysis-targeting chimeras (PROTACs) inefficient for tubulin degradation. Further research is needed to apply PROTACs to tubulin homeostasis.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Microtubule and tubulin dysregulation is implicated in various diseases, including cancer.
- Existing microtubule agents face resistance, limiting their clinical efficacy.
- Novel therapeutic strategies targeting tubulin are needed.
Purpose of the Study:
- To develop and evaluate tubulin-targeted small molecule degraders.
- To investigate the potential of proteolysis-targeting chimeras (PROTACs) for tubulin degradation.
- To explore new avenues for overcoming resistance to anti-cancer agents.
Main Methods:
- Design and synthesis of novel α- and β-tubulin degraders.
- Utilizing microtubule-destabilizing agents as scaffolds for degrader development.
- Testing cereblon-recruiting PROTACs for their efficiency in inducing tubulin degradation.
Main Results:
- Several series of tubulin degraders were synthesized and examined.
- Previously reported covalent tubulin binders induced tubulin degradation.
- Cereblon-recruiting PROTACs demonstrated inefficiency in degrading tubulin in this study.
Conclusions:
- Tubulin degraders show promise as tools for studying tubulin homeostasis.
- The PROTAC strategy's applicability to tubulin, a clinically relevant target, requires further investigation.
- Overcoming resistance to anti-cancer agents may benefit from novel degradation-based approaches.
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