TY - JOUR
T1 - A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders
T2 - Proof-of-Concept Application to BRD4-Degrading PROTACs
AU - Bhela, Irene Preet
AU - Ranza, Alice
AU - Balestrero, Federica Carolina
AU - Serafini, Marta
AU - Aprile, Silvio
AU - Di Martino, Rita Maria Concetta
AU - Condorelli, Fabrizio
AU - Pirali, Tracey
N1 - Publisher Copyright:
© 2022 Authors. All rights reserved.
PY - 2022/11/24
Y1 - 2022/11/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85141592921&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.2c01218
DO - 10.1021/acs.jmedchem.2c01218
M3 - Article
SN - 0022-2623
VL - 65
SP - 15282
EP - 15299
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 22
ER -