PXD056865-1

PXD056865 is an original dataset announced via ProteomeXchange.

Title	Discovery of Novel Choline Kinase Inhibitors Using Integrated Phenotypic and Target Profiling
Description	Choline 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.
HostingRepository	PRIDE
AnnounceDate	2025-01-27
AnnouncementXML	Submission_2025-01-27_12:08:36.197.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ludwig Bauer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-16 10:52:19	ID requested
⏵ 1	2025-01-27 12:08:37	announced
2	2025-01-29 04:44:43	announced	2025-01-29: Updated project metadata.

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]

submitter keyword: Chemical Proteomics

Kilian Huber
contact affiliation	Centre for Medicines Discovery & Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
contact email	kilian.huber@cmd.ox.ac.uk
lab head
Ludwig Bauer
contact affiliation	University of Oxford
contact email	ludwig.bauer@st-hughs.ox.ac.uk
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/2025/01/PXD056865

PRIDE project URI

• PRIDE
  1. PXD056865
     1. Label: PRIDE project
     2. Name: Discovery of Novel Choline Kinase Inhibitors Using Integrated Phenotypic and Target Profiling