Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 22, Pages 15282-15299Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01218
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Funding
- Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR) [2017WJZ9W9]
- Fondazione AIRC (Associazione Italiana per la Ricerca sul Cancro) [2017WJZ9W9]
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The study presents a novel platform that combines multicomponent reactions and protein degraders to prepare highly decorated PROTACs. By applying this platform to BRD4 degradation, a set of degraders with high efficiency was discovered. This approach provides a versatile and cost-effective means to access libraries of protein degraders and increase the chance of identifying successful candidates.
The use of small molecules to induce targeted protein degradation is increasingly growing in the drug discovery landscape, and protein degraders have progressed rapidly through the pipelines. Despite the advances made so far, their synthesis still represents a significant burden and new approaches are highly demanded. Herein we report an unprecedented platform that leverages the modular nature of both multicomponent reactions and degraders to enable the preparation of highly decorated PROTACs. As a proof of principle, our platform has been applied to the preparation of potential BRD4-degrading PROTACs, resulting in the discovery of a set of degraders endowed with high degradation efficiency. Compared to the existing methods, our approach offers a versatile and cost-effective means to access libraries of protein degraders and increase the chance of identifying successful candidates.
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