Phenomics‐Based Discovery of Novel Orthosteric Choline Kinase Inhibitors
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.
Authors
- Sarantos Kostidis (ORCID: https://orcid.org/0000-0002-2040-2563)
- H. Ümit Kanıskan (ORCID: https://orcid.org/0000-0001-5327-832X)
- Ludwig G. Bauer (ORCID: https://orcid.org/0000-0002-2235-3945)
- Sonja Sievers (ORCID: https://orcid.org/0000-0003-0854-4507)
- Yvonne Sundström
- Catherine Rogers (ORCID: https://orcid.org/0000-0001-7005-4459)
- Martin Giera (ORCID: https://orcid.org/0000-0003-1684-1894)
- Alejandro Gonzalez Orta
- Jian Jun Jin (ORCID: https://orcid.org/0000-0002-2387-3862)
- Michael Sundström
- Jennifer Ward (ORCID: https://orcid.org/0000-0002-8735-5263)
- Herbert Waldmann (ORCID: https://orcid.org/0000-0002-9606-7247)
- Louise Berg (ORCID: https://orcid.org/0000-0001-6538-2837)
- K. Huber (ORCID: https://orcid.org/0000-0002-1103-5300)
- Jianping Hu (ORCID: https://orcid.org/0000-0001-7367-3968)
- Tuomas Tolvanen (ORCID: https://orcid.org/0000-0002-3581-208X)
- Ioanna Panagakou
- Elisabeth M. Rothweiler (ORCID: https://orcid.org/0000-0003-3303-2044)
- Usha Singh (ORCID: https://orcid.org/0000-0003-4177-0848)
- Juan Carlos Alarcón Barrera
Institutions
- Leiden University (NL)
- Karolinska University Hospital (SE)
- Discovery Centre (CA)
- Nuffield Orthopaedic Centre (GB)
- Structural Genomics Consortium (CA)
- Karolinska Institutet (SE)
- University of Oxford (GB)
- Netherlands Metabolomics Centre (NL)
- Max Planck Institute of Molecular Physiology (DE)
- Pelago Bioscience (Sweden) (SE)
- Oxford BioMedica (United Kingdom) (GB)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1002/anie.202420149
- Citations
- 1
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 0.36
Funders
- Departamento Administrativo de Ciencia, Tecnología e Innovación (COLCIENCIAS)
- McGill University
- Diamond Light Source
- European Federation of Pharmaceutical Industries and Associations
- University of Oxford
- European Commission
- Max-Planck-Gesellschaft
- H2020 European Research Council