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Neuritogenic Militarinone‐Inspired 4‐Hydroxypyridones Target the Stress Pathway Kinase MAP4K4
Author(s) -
Schröder Peter,
Förster Tim,
Kleine Stefan,
Becker Christian,
Richters André,
Ziegler Slava,
Rauh Daniel,
Kumar Kamal,
Waldmann Herbert
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201501515
Subject(s) - microbiology and biotechnology , kinase , stress (linguistics) , chemistry , biology , linguistics , philosophy
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.