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PXD056865-1

PXD056865 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleDiscovery of Novel Choline Kinase Inhibitors Using Integrated Phenotypic and Target Profiling
DescriptionCholine kinase alpha (CHKA) is a central mediator of cell metabolism linked to cancer and immune regulation. Cellular and clinical evaluation of CHKA has been hampered by challenges in the development of drug-like choline kinase inhibitors. Here, we identify CHKA as an unexpected off-target of histone methyltransferase inhibitors using an integrated phenotypic and systems pharmacology approach. We confirm CHKA as a direct protein target of the compounds UNC0638 and UNC0737 using a combination of chemoproteomic, biochemical, cellular, and metabolic profiling assays, possibly explaining the previously reported discrepancies observed for different G9a/GLP inhibitor scaffolds in cellular assays. Using primary human cell model systems, we discover that CHKA modulation plays a crucial part in IgG secretion and B-cell maturation in line with a role for CHKA to regulate immune signalling. Co-crystal structures of UNC0638 and UNC0737 with CHKA unravel an unusual binding mode and suggest the inhibitors as attractive starting points for the development of selective chemical tools to further explore the biological role of CHKA in cancer and immune metabolism.
HostingRepositoryPRIDE
AnnounceDate2025-01-27
AnnouncementXMLSubmission_2025-01-27_12:08:36.197.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterLudwig Bauer
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListiodoacetamide derivatized residue
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02024-10-16 10:52:19ID requested
12025-01-27 12:08:37announced
22025-01-29 04:44:43announced2025-01-29: Updated project metadata.
Publication List
10.1002/anie.202420149;
Bauer LG, Ward JA, D, í, az-S, á, ez L, Sundstr, ö, m Y, Tolvanen T, Alarc, ó, n Barrera JC, Kostidis S, Rogers CM, Panagakou I, Singh U, Rothweiler EM, Gonzalez Orta A, Kaniskan H Ü, Hu J, Jin J, Sievers S, Waldmann H, Giera M, Sundstr, ö, m M, Berg L, Huber KVM, Phenomics-Based Discovery of Novel Orthosteric Choline Kinase Inhibitors. Angew Chem Int Ed Engl, 64(7):e202420149(2025) [pubmed]
Keyword List
submitter keyword: Chemical Proteomics
Contact List
Kilian Huber
contact affiliationCentre for Medicines Discovery & Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
contact emailkilian.huber@cmd.ox.ac.uk
lab head
Ludwig Bauer
contact affiliationUniversity of Oxford
contact emailludwig.bauer@st-hughs.ox.ac.uk
dataset submitter
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Dataset FTP location
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