Related Experiment Video
Updated: Jun 4, 2025

Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach
Published on: February 21, 2019
Phenomics-Based Discovery of Novel Orthosteric Choline Kinase Inhibitors
Ludwig G Bauer1,2, Jennifer A Ward1,2, Laura Díaz-Sáez1,2
1Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
Abstract:
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 phenomic approach. We confirm CHKA as a direct protein target of the aminoquinazolines 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 impairs IgG secretion and B-cell maturation consistent with the notion that choline metabolism plays an important role in immune signalling. Co-crystal structures of UNC0638 and UNC0737 with CHKA unravel an unexpected 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.
More Related Videos
08:49Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
07:18A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening
Published on: May 12, 2017
Related Concept Videos
Indirect-Acting Cholinergic Agonists: Mechanism of Action
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Drug Discovery: Overview
Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
The direct-acting...
Direct-Acting Cholinergic Agonists: Pharmacokinetics