Phenomics-based Discovery of Novel Orthosteric Choline Kinase Inhibitors

Ludwig G Bauer; Jennifer A Ward; Laura Díaz-Sáez; Yvonne Sundström; Tuomas Tolvanen; Juan Carlos Alarcón Barrera; Sarantos Kostidis; Catherine M Rogers; Ioanna Panagakou; Usha Singh; Elisabeth M Rothweiler; Alejandro Gonzalez Orta; H Ümit Kaniskan; Jianping Hu; Jian Jin; Sonja Sievers; Herbert Waldmann; Martin Giera; Michael Sundström; Louise Berg; Kilian Huber

doi:10.1002/anie.202420149

Phenomics-based Discovery of Novel Orthosteric Choline Kinase Inhibitors

Angew Chem Int Ed Engl. 2024 Dec 30:e202420149. doi: 10.1002/anie.202420149. Online ahead of print.

Authors

Ludwig G Bauer¹, Jennifer A Ward¹, Laura Díaz-Sáez², Yvonne Sundström³, Tuomas Tolvanen⁴, Juan Carlos Alarcón Barrera⁵, Sarantos Kostidis⁵, Catherine M Rogers¹, Ioanna Panagakou⁶, Usha Singh¹, Elisabeth M Rothweiler¹, Alejandro Gonzalez Orta¹, H Ümit Kaniskan⁷, Jianping Hu⁷, Jian Jin⁷, Sonja Sievers⁸, Herbert Waldmann⁹, Martin Giera¹⁰, Michael Sundström⁴, Louise Berg⁴, Kilian Huber¹¹

Affiliations

¹ University of Oxford, Nuffield Department of Medicine, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
² University of Oxford, Nuffield Department of Mediciney, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
³ Karolinska Institutet, Department of Medicine Solna, SWEDEN.
⁴ Karolinska Institutet, Structural Genomics Consortium, SWEDEN.
⁵ Leiden University: Universiteit Leiden, Center for Proteomics and Metabolomics, NETHERLANDS, KINGDOM OF THE.
⁶ University of Oxford, Centre for Medicines Discovery, Nuffield Department of Medicine, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
⁷ Icahn School of Medicine at Mount Sinai, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, UNITED STATES OF AMERICA.
⁸ Max-Planck-Institute of Molecular Physiology Department of Chemical Biology: Max Planck Institut fur Molekulare Physiologie Abteilung Chemische Biologie, Compound Management and Screening Center at the Max Planck Institute of Molecular Physiology, GERMANY.
⁹ Max-Planck-Institute of Molecular Physiology Department of Chemical Biology: Max Planck Institut fur Molekulare Physiologie Abteilung Chemische Biologie, Department of Chemical Biology, GERMANY.
¹⁰ University of Leiden: Universiteit Leiden, Center for Proteomics and Metabolomics, NETHERLANDS, KINGDOM OF THE.
¹¹ University of Oxford, Nuffield Department of Medicine, Centre for Medicines Discovery, NDM Research Building, Roosevelt Drive, OX3 7FZ, Oxford, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.

PMID: 39740997
DOI: 10.1002/anie.202420149

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.

Keywords: cell painting; chemical probes; chemical proteomics; metabolomics; phenotypic.