Bauer Ludwig G, Ward Jennifer A, Díaz-Sáez Laura, Sundström Yvonne, Tolvanen Tuomas, Alarcón Barrera Juan Carlos, Kostidis Sarantos, Rogers Catherine M, Panagakou Ioanna, Singh Usha, Rothweiler Elisabeth M, Gonzalez Orta Alejandro, Kaniskan H Ümit, Hu Jianping, Jin Jian, Sievers Sonja, Waldmann Herbert, Giera Martin, Sundström Michael, Berg Louise, Huber Kilian V M
Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
Angew Chem Int Ed Engl. 2025 Feb 10;64(7):e202420149. doi: 10.1002/anie.202420149. Epub 2025 Jan 13.
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.
胆碱激酶α（CHKA）是细胞代谢的核心调节因子，与癌症和免疫调节相关。由于类药物胆碱激酶抑制剂开发面临挑战，CHKA的细胞和临床评估受到阻碍。在此，我们使用整合表型组学方法，将CHKA鉴定为组蛋白甲基转移酶抑制剂意外的脱靶蛋白。我们通过化学蛋白质组学、生化、细胞和代谢谱分析相结合的方法，确认CHKA是氨基喹唑啉类化合物UNC0638和UNC0737的直接蛋白质靶点，这可能解释了之前在细胞实验中观察到的不同G9a/GLP抑制剂支架的差异。使用原代人类细胞模型系统，我们发现CHKA调节会损害IgG分泌和B细胞成熟，这与胆碱代谢在免疫信号传导中起重要作用的观点一致。UNC0638和UNC0737与CHKA的共晶体结构揭示了一种意外的结合模式，并表明这些抑制剂是开发选择性化学工具以进一步探索CHKA在癌症和免疫代谢中的生物学作用的有吸引力的起点。
