Targeted degradation via direct 26S proteasome recruitment

Autor: Charlene Bashore, Sumit Prakash, Matthew C. Johnson, Ryan J. Conrad, Ivy A. Kekessie, Suzie J. Scales, Noriko Ishisoko, Tracy Kleinheinz, Peter S. Liu, Nataliya Popovych, Aaron T. Wecksler, Lijuan Zhou, Christine Tam, Inna Zilberleyb, Rajini Srinivasan, Robert A. Blake, Aimin Song, Steven T. Staben, Yingnan Zhang, David Arnott, Wayne J. Fairbrother, Scott A. Foster, Ingrid E. Wertz, Claudio Ciferri, Erin C. Dueber
Rok vydání: 2022
Předmět:
Zdroj: Nature Chemical Biology. 19:55-63
ISSN: 1552-4469
1552-4450
Popis: Engineered destruction of target proteins by recruitment to the cell’s degradation machinery has emerged as a promising strategy in drug discovery. The majority of molecules that facilitate targeted degradation do so via a select number of ubiquitin ligases, restricting this therapeutic approach to tissue types that express the requisite ligase. Here, we describe a new strategy of targeted protein degradation through direct substrate recruitment to the 26S proteasome. The proteolytic complex is essential and abundantly expressed in all cells; however, proteasomal ligands remain scarce. We identify potent peptidic macrocycles that bind directly to the 26S proteasome subunit PSMD2, with a 2.5-Å-resolution cryo-electron microscopy complex structure revealing a binding site near the 26S pore. Conjugation of this macrocycle to a potent BRD4 ligand enabled generation of chimeric molecules that effectively degrade BRD4 in cells, thus demonstrating that degradation via direct proteasomal recruitment is a viable strategy for targeted protein degradation.
Databáze: OpenAIRE
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