2. Academic Validation
  3. Selective inhibitors of the FK506-binding protein 51 by induced fit

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

  • Nat Chem Biol. 2015 Jan;11(1):33-7. doi: 10.1038/nchembio.1699.
Steffen Gaali 1,  Alexander Kirschner 1,  Serena Cuboni 1,  Jakob Hartmann 2,  Christian Kozany 1,  Georgia Balsevich 2,  Christian Namendorf 1,  Paula Fernandez-Vizarra 2,  Claudia Sippel 1,  Anthony S Zannas 3,  Rika Draenert 4,  Elisabeth B Binder 5,  Osborne F X Almeida 2,  Gerd Rühter 6,  Manfred Uhr 1,  Mathias V Schmidt 2,  Chadi Touma 2,  Andreas Bracher 7,  Felix Hausch 1
Affiliations

Affiliations

  • 1 Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
  • 2 Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
  • 3 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.
  • 4 Medizinische Klinik und Poliklinik IV, Hospital of the University of Munich, Munich, Germany.
  • 5 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.
  • 6 Lead Discovery Center GmbH, Dortmund, Germany.
  • 7 Max Planck Institute of Biochemistry, Martinsried, Germany.
PMID: 25436518 DOI: 10.1038/nchembio.1699
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.

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