Bridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable Targets.

ABSTRACT: Proteolysis Targeting Chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While many PROTACs have been developed for numerous protein targets, current small-molecule PROTAC approaches cannot target undruggable proteins that do not have small-molecule binders. Here, we present a novel PROTAC approach, termed bridged PROTAC, which utilizes a small-molecule binder of the target protein's binding partner to recruit the protein complex into close proximity with an E3 ubiquitin ligase to target undruggable proteins. Applying this bridged PROTAC strategy, we discovered MS28, the first-in-class degrader of cyclin D1, which lacks a small-molecule binder. MS28 effectively degrades cyclin D1, with faster degradation kinetics and superior degradation effici

SUBMITTER: Xiong Y 

PROVIDER: S-EPMC9772293 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature