Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Straße 11, 44227 Dortmund (Germany).
Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Straße 6, 44221 Dortmund (Germany).
Angew Chem Int Ed Engl. 2015 Oct 12;54(42):12398-403. doi: 10.1002/anie.201501515. Epub 2015 Apr 23.
Progressive loss and impaired restoration of neuronal activity are hallmarks of neurological diseases, and new small molecules with neurotrophic activity are in high demand. The militarinone alkaloids and structurally simplified analogues with 4-hydroxy-2-pyridone core structure induce pronounced neurite outgrowth, but their protein target has not been identified. Reported herein is the synthesis of a militarinone-inspired 4-hydroxy-2-pyridone collection, its investigation for enhancement of neurite outgrowth, and the discovery of the stress pathway kinase MAP4K4 as a target of the discovered neuritogenic pyridones. The most potent 4-hydroxy-2-pyridone is a selective ATP-competitive inhibitor of MAP4K4 but not of the other stress pathway related kinases, as proven by biochemical analysis and by a crystal structure of the inhibitor in complex with MAP4K4. The findings support the notion that MAP4K4 may be a new target for the treatment of neurodegenerative diseases.
进行性神经元活动丧失和受损是神经退行性疾病的标志，因此人们急需具有神经营养活性的新型小分子。马藤灵酮生物碱及其具有 4-羟基-2-吡啶酮核心结构的结构简化类似物可诱导明显的神经突生长，但它们的蛋白质靶标尚未确定。本文报道了马藤灵酮启发的 4-羟基-2-吡啶酮化合物的合成、对神经突生长的增强作用的研究，以及发现应激途径激酶 MAP4K4 作为发现的神经营养吡啶酮的靶标。最有效的 4-羟基-2-吡啶酮是 MAP4K4 的选择性 ATP 竞争性抑制剂，但不是其他应激途径相关激酶的抑制剂，这一点通过生化分析和抑制剂与 MAP4K4 的晶体结构证明。这些发现支持了 MAP4K4 可能是治疗神经退行性疾病的新靶标的观点。
