PXD017387-1
PXD017387 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Enhancing Intracellular Concentration and Target Engagement of PROTACs with Reversible Covalent Chemistry |
| Description | Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing the appropriate E3 ligase for a certain targeted protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, it is well known that due to the large sizes of PROTAC molecules, their cellular uptake level remains an issue, posing a challenge to translate PROTACs into therapeutics. Driven by our fundamental investigation to compare how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, may affect the degradation of a model protein Bruton's Tyrosine Kinase (BTK), we serendipitously discovered that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular concentration and target engagement of the PROTAC. Building on this discovery, we developed RC-1 as the first reversible covalent BTK PROTAC, which has high target occupancy and is effective as both an inhibitor and a degrader. Molecular dynamics calculations and phase-separation based ternary complex assays support that RC-1 forms a stable ternary complex with BTK and Cereblon (CRBN). Additionally, RC-1 compares favorably with other reported BTK degraders in cell viability and target engagement assays and has a reasonable plasma half-life for in vivo applications. Importantly, this reversible covalent strategy can be generalized and applied to improve other PROTACs. This work can not only help to develop optimal BTK degraders for clinical applications but also provide a new strategy to improve PROTAC efficacy. |
| HostingRepository | MassIVE |
| AnnounceDate | 2020-06-27 |
| AnnouncementXML | Submission_2020-06-27_10:40:30.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 | TMT6plex; Oxidation |
| Instrument | Orbitrap Fusion Lumos |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2020-02-04 23:00:44 | ID requested | |
| ⏵ 1 | 2020-06-27 10:40:30 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: PROTAC, BTK, CRBN, Reversible Covalent, Target Engagement |
Contact List
| Jin Wang | |
|---|---|
| contact affiliation | Baylor College of Medicine, Houston TX |
| contact email | wangj@bcm.edu |
| 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/MSV000084902/ |
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