title: Neuritogenic militarinone-inspired 4-hydroxypyridones target the stress pathway kinase MAP4K4.
abstract: 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.
authors.affiliation: 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).
authors.forename: Peter
authors.initials: P
authors.lastname: Schröder
authors.affiliation: 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).
authors.forename: Tim
authors.initials: T
authors.lastname: Förster
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Straße 6, 44221 Dortmund (Germany).
authors.forename: Stefan
authors.initials: S
authors.lastname: Kleine
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Straße 6, 44221 Dortmund (Germany).
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Straße 6, 44221 Dortmund (Germany).
authors.forename: André
authors.initials: A
authors.lastname: Richters
authors.affiliation: Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Straße 11, 44227 Dortmund (Germany).
authors.forename: Slava
authors.initials: S
authors.lastname: Ziegler
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Straße 6, 44221 Dortmund (Germany).
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
authors.affiliation: 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).
authors.forename: Kamal
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Straße 11, 44227 Dortmund (Germany). herbert.waldmann@mpi-dortmund.mpg.de.|Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Straße 6, 44221 Dortmund (Germany). herbert.waldmann@mpi-dortmund.mpg.de.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C449040:militarinone A; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: alkaloids; biological activity; drug discovery; natural products; neurological agents