Neuritogenic Militarinone‐Inspired 4‐Hydroxypyridones Target the Stress Pathway Kinase MAP4K41. Issue 42 (23rd April 2015)

• Record Type: Journal Article
• Authors: Schröder, Peter; Förster, Tim; Kleine, Stefan; Becker, Christian; Richters, André; Ziegler, Slava; Rauh, Daniel; Kumar, Kamal; Waldmann, Herbert
• Is Part Of: Angewandte Chemie international edition. Volume 54:Issue 42(2015)
• Page Start: 12398
• Page End: 12403
• Publication Date: 2015-04-23
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201501515
• Languages: English
• ISSNs: 1433-7851

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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.</p> </abstract>