Targeted Protein Degradation through Recruitment of the CUL4A Complex Adaptor Protein DDB1.

ABSTRACT: Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional Proteolysis Targeting Chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ubiquitin ligases, such as cereblon and VHL. However, previous studies have surprisingly uncovered molecular glue degraders that exploit a CUL4A adaptor protein DDB1 to degrade neosubstrate proteins. Here, we sought to investigate whether DDB1 recruiters can be discovered that can be exploited for PROTAC applications. We utilized activity-based protein profiling and cysteine chemoproteomic screening to identify a covalent recruiter that targets C173 on DDB1 and exploited this recruiter to develop PROTACs against BRD4 and androgen receptor (AR). We

SUBMITTER: Meyers M 

PROVIDER: S-EPMC10443223 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature