PXD052975
PXD052975 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Discovery of Monovalent Direct Degraders of BRD4 That Act Via the Recruitment of DCAF11 |
| Description | 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. |
| HostingRepository | MassIVE |
| AnnounceDate | 2025-03-10 |
| AnnouncementXML | Submission_2025-03-10_21:40:43.195.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Alexandre Rosa Campos |
| SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
| ModificationList | Oxidation; Acetyl; TMTpro |
| Instrument | Orbitrap Fusion Lumos |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2024-06-10 14:36:19 | ID requested | |
| ⏵ 1 | 2025-03-10 21:40:43 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: Targeted protein degradation, Monovalent Degrader, Bromodomain extra-terminal (BET) protein, DCAF11 |
Contact List
| Gregory S. Parker | |
|---|---|
| contact affiliation | Plexium |
| contact email | greg.parker@plexium.com |
| lab head | |
| Alexandre Rosa Campos | |
| contact affiliation | SBP Medical Discovery Institute |
| contact email | arosacampos@sbpdiscovery.org |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive.ucsd.edu/v08/MSV000094973/ |
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