title: Selective inhibitors of the FK506-binding protein 51 by induced fit.
abstract: The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants.
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Gaali
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kirschner
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Serena
authors.initials: S
authors.lastname: Cuboni
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hartmann
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kozany
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Georgia
authors.initials: G
authors.lastname: Balsevich
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Namendorf
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Paula
authors.identifier: 0000000203226844
authors.initials: P
authors.lastname: Fernandez-Vizarra
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sippel
authors.affiliation: 1] Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. [2] Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Zannas
authors.affiliation: Medizinische Klinik und Poliklinik IV, Hospital of the University of Munich, Munich, Germany.
authors.forename: Rika
authors.initials: R
authors.lastname: Draenert
authors.affiliation: 1] Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. [2] Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Osborne F X
authors.initials: OF
authors.lastname: Almeida
authors.affiliation: Lead Discovery Center GmbH, Dortmund, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Rühter
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Mathias V
authors.identifier: 0000000237882268
authors.initials: MV
authors.lastname: Schmidt
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Chadi
authors.initials: C
authors.lastname: Touma
authors.affiliation: Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Andreas
authors.identifier: 0000000185307594
authors.initials: A
authors.lastname: Bracher
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
mesh_terms: D000223:Adaptation, Psychological / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D002478:Cells, Cultured; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D016501:Neurites / Q000187:drug effects; D011487:Protein Conformation; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000928:Antidepressive Agents; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C403485:tacrolimus binding protein 4