Selective inhibitors of the FK506-binding protein 51 by induced fit

Gaali, Steffen; Kirschner, Alexander; Cuboni, Serena; Hartmann, Jakob; Kozany, Christian; Balsevich, Georgia; Namendorf, Christian; Fernandez-Vizarra, Paula; Sippel, Claudia; Zannas, Anthony S.; Draenert, Rika; Binder, Elisabeth B.; Almeida, Osborne F. X.; Ruehter, Gerd; Uhr, Manfred; Schmidt, Mathias V.; Touma, Chadi; Bracher, Andreas; Hausch, Felix

doi:10.1038/nchembio.1699

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Selective inhibitors of the FK506-binding protein 51 by induced fit

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Gaali, Steffen
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons182844

Kirschner, Alexander
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80290

Cuboni, Serena
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80354

Hartmann, Jakob
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80406

Kozany, Christian
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons136275

Balsevich, Georgia
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80456

Namendorf, Christian
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons187775

Fernandez-Vizarra, Paula
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons136431

Sippel, Claudia
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons160236

Zannas, Anthony S.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80272

Binder, Elisabeth B.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80249

Almeida, Osborne F. X.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80563

Uhr, Manfred
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80514

Schmidt, Mathias V.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80557

Touma, Chadi
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80356

Hausch, Felix
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Gaali, S., Kirschner, A., Cuboni, S., Hartmann, J., Kozany, C., Balsevich, G., et al. (2015). Selective inhibitors of the FK506-binding protein 51 by induced fit. NATURE CHEMICAL BIOLOGY, 11(1), 33-+. doi:10.1038/nchembio.1699.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0029-2B7F-9

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.