PXD069506 is an
original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Discovery of an Enantioselective Covalent Inhibitor of BAX for Cytoprotection in Vivo |
| Description | The pro-apoptotic BCL-2 protein BAX is a central executioner of mitochondrial apoptosis and a driver of acute and chronic cell loss in diverse human diseases. The C126 residue of BAX lies within a key regulatory region and its derivatization by physiologic and pharmacologic ligands can alternatively activate or inhibit BAX function. Here, we report the discovery of an enantioselective covalent BAX inhibitor that confers cytoprotection across multiple cell types and in vivo. Chemoproteomic screening identified tryptoline acrylamide stereoprobes that derivatized BAX at C126 with high selectivity, constraining its conformation, and suppressing apoptosis in a strictly BAX-dependent manner, as confirmed by genetic knockout models. Medicinal chemistry optimization yielded covalent BAX inhibitor 3 (CBI-3), a more stable analog with retained enantioselectivity, improved pharmacokinetics, and dose-responsive cytoprotective activity against ABT-737 and cisplatin-induced apoptosis without intrinsic toxicity. In a murine model of Fas-induced fulminant hepatic failure, CBI-3 significantly reduced hepatocyte apoptosis and preserved liver histology and animal survival, nearly phenocopying Bax deletion. These findings establish enantioselective covalent inhibition of BAX as a viable strategy for cytoprotection with demonstrable in vivo efficacy, opening the door to next-generation therapeutics that directly block pathologic cell death. |
| HostingRepository | PRIDE |
| AnnounceDate | 2026-06-28 |
| AnnouncementXML | Submission_2026-06-27_21:59:24.474.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Thomas Wales |
| SpeciesList | scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090; |
| ModificationList | No PTMs are included in the dataset |
| Instrument | Synapt MS |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|
| 0 | 2025-10-15 19:21:28 | ID requested | |
| ⏵ 1 | 2026-06-27 21:59:24 | announced | |
Publication List
| Dataset with its publication pending |
Keyword List
| submitter keyword: BAX |
| HDX-MS |
| hydrogen/deuterium exchange mass spectrometry |
| covalent inhibitor |
Contact List
| Thomas E. Wales |
|---|
| contact affiliation | Northeastern University |
| contact email | t.wales@northeastern.edu |
| lab head | |
| Thomas Wales |
|---|
| contact affiliation | Northeastern University |
| contact email | t.wales@northeastern.edu |
| dataset submitter | |
Full Dataset Link List
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://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD069506 |
| PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD069506
- Label: PRIDE project
- Name: Discovery of an Enantioselective Covalent Inhibitor of BAX for Cytoprotection in Vivo
