PXD054470

PXD054470 is an original dataset announced via ProteomeXchange.

Title	Thioamide-warheads with enhanced cysteine reactivity and specificity for targeted covalent inhibitors
Description	Targeted covalent inhibitors (TCIs) form covalent bond with their target that requires tailored reactive functionalities identified as warheads. Here we present a versatile approach changing carboxamide functions with thioamides that transforms known warheads to softer electrophiles enhancing reactivity and specificity for covalent cysteine modification. Furthermore, the oxygen-sulfur (O-S) exchange led to the discovery of new electrophilic warhead chemotypes such as chloroethanethioamides and fluoroethanethioamides. The improved reactivity and specificity of thioamide warheads were demonstrated in comparative labelling experiments of carboxamide and thioamide ibrutinib analogues at BTK. Additionally, we synthesized and evaluated alkyne-tagged thioamide derivatives in chemoproteomic applications. In addition to the increased reactivity observed at the proteome level, the chloroethanethioamide probe preferentially labeled a different subset of the proteome compared to iodoacetamide. Our findings suggest that thioamide warheads are suitable for TCI development and chemical biology applications, offering alternative cysteine-specific chemotypes for future covalent probe design.
HostingRepository	PRIDE
AnnounceDate	2026-09-07
AnnouncementXML	Submission_2026-09-06_16:31:51.631.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ronen Gabizon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 240

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-31 21:16:01	ID requested
⏵ 1	2026-09-06 16:31:52	announced

10.1038/s41467-026-72993-6;

Petri L, Gabizon R, P, é, czka N, Á, br, á, nyi-Balogh P, Simon J, Imre T, Ferenczy GG, London N, Keser, ű GM, -Halothioamide warheads with enhanced cysteine reactivity and specificity for covalent protein labelling. Nat Commun, 17(1):(2026) [pubmed]

submitter keyword: warhead, proteomics,cystein, covalent inhibitors

Nir London
contact affiliation	Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
contact email	nir.london@weizmann.ac.il
lab head
Ronen Gabizon
contact affiliation	Department of Chemical and Structural Biology, Weizmann Institute of Science
contact email	ronen.gabizon@weizmann.ac.il
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054470
     1. Label: PRIDE project
     2. Name: Thioamide-warheads with enhanced cysteine reactivity and specificity for targeted covalent inhibitors