Proteomics

Dataset Information

0

Discovery of Monovalent Direct Degraders of BRD4 That Act Via the Recruitment of DCAF11


ABSTRACT: Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent direct degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex. Using an ultra-high throughput cell-based screening platform, degraders of the bromodomain extra-terminal (BET) protein BRD4 were identified and optimized to yield a lead compound, PLX-3618. In this paper, we demonstrate that PLX-3618 elicited UPS-mediated selective degradation of BRD4, resulting in potent anti-tumor activity in vitro and in vivo. Characterization of the degradation mechanism identified DCAF11 as the E3 ligase required for PLX-3618-mediated degradation of BRD4. Protein-protein interaction studies verified a BRD4:PLX-3618:DCAF11 ternary complex, and mutational studies provided further insights into the DCAF11-mediated degradation mechanism. Collectively, these results demonstrate the discovery and characterization of a novel small molecule that selectively degrades BRD4 through the recruitment of the E3 substrate receptor, DCAF11, and promotes potent anti-tumor activity in vivo.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Gregory S. Parker  

PROVIDER: MSV000094973 | MassIVE | Mon Jun 10 14:36:00 BST 2024

SECONDARY ACCESSION(S): PXD052975

REPOSITORIES: MassIVE

Dataset's files

Source:
Action DRS
Other
Items per page:
1 - 1 of 1

Similar Datasets

2021-02-12 | GSE162205 | GEO
2024-01-08 | PXD040570 | Pride
2022-10-13 | PXD022399 | Pride
2016-04-01 | E-GEOD-79253 | biostudies-arrayexpress
2024-05-17 | GSE243615 | GEO
2022-09-07 | PXD034424 | Pride
2022-09-07 | PXD034378 | Pride
2022-09-07 | PXD034423 | Pride
2018-05-23 | PXD008674 | Pride
2018-05-16 | PXD008689 | Pride