PXD064073

PXD064073 is an original dataset announced via ProteomeXchange.

Title	Modular Vinyl-Phosphonamidates for Cysteine Directed Protein Targeting
Description	Covalent inhibitors and chemical probes targeting ligandable cysteine residues have emerged as powerful tools in drug discovery and proteomics. In this study, we introduce vinyl-phosphonamidates (VPAs) as a novel class of latent cysteine electrophiles and assess their reactivity, selectivity, and potential for developing covalent inhibitors. Compared to well-established chloroacetamide and acrylamide electrophiles VPAs exhibit a significantly lower intrinsic reactivity towards the model thiol glutathione. Moreover, VPA-derived covalent fragments displayed only very limited non-specific reactivity in human cell lysate. Encouraged by these results, we developed VPA-functionalized derivatives of the FDA-approved covalent inhibitors Afatinib and Ibrutinib and evaluated their ability to engage the target protein by gel-based and mass spectrometry-based activity based protein profiling (ABPP). Compared to commonly employed Michael-acceptor based electrophilic groups, PA-functionalized drug ligands displayed significantly less off-targets while maintaining inhibitor efficiency. Furthermore, we leveraged the modular nature and accessibility of VPAs to develop a bifunctional proteolysis-targeting chimera (PROTAC) for targeted protein degradation. The demonstrated selectivity and modularity, as exemplified by the incorporation of various ligands on the phosphorus O-substituent, of the vinyl-phosphonamidate group as a cysteine-directed electrophile highlights its ability to expand the chemical space in the development of covalent inhibitors with a favourable proteome-wide reactivity profile.
HostingRepository	PRIDE
AnnounceDate	2026-03-09
AnnouncementXML	Submission_2026-03-08_18:16:09.142.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christian Stieger
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-19 16:22:03	ID requested
⏵ 1	2026-03-08 18:16:10	announced

Stieger CE, V, ö, lkel C, Bertelsen MB, Lisurek M, Arafiles JVV, Franke J, Crocker L, Schuppe K, Lim Y, Groneberg C, Christmann M, Sun H, Hackenberger CPR, Modular Vinyl Phosphonamidates for Cysteine-Directed Protein Targeting. J Am Chem Soc, 148(7):7772-7781(2026) [pubmed]

10.1021/jacs.5c22349;

submitter keyword: Chemoproteomics, covalent inhibitors

Christian P.R. Hackenberger
contact affiliation	Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)Berlin
contact email	hackenbe@fmp-berlin.de
lab head
Christian Stieger
contact affiliation	FMP Belrin
contact email	stieger@fmp-berlin.de
dataset submitter

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/2026/03/PXD064073

PRIDE project URI

• PRIDE
  1. PXD064073
     1. Label: PRIDE project
     2. Name: Modular Vinyl-Phosphonamidates for Cysteine Directed Protein Targeting