A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders: Proof-of-Concept Application to BRD4-Degrading PROTACs

Irene Preet Bhela, Alice Ranza, Federica Carolina Balestrero, Marta Serafini, Silvio Aprile, Rita Maria Concetta Di Martino, Fabrizio Condorelli, Tracey Pirali

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

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.

Lingua originaleInglese
pagine (da-a)15282-15299
Numero di pagine18
RivistaJournal of Medicinal Chemistry
Volume65
Numero di pubblicazione22
DOI
Stato di pubblicazionePubblicato - 24 nov 2022

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