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

Nature Chemical Biology volume 11, pages 33–37 (2015)Cite this article

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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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Figure 1: Selective inhibition of FKBP51 or FKBP52 inversely affects neurite outgrowth.
Figure 2: Induced-fit binding of selective FKBP51 inhibitors.
Figure 3: Selective inhibition of FKBP51 enhances neurite outgrowth.
Figure 4: SAFit2 enhances regulation of stress hormone secretion and active stress-coping behavior in mice.

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Acknowledgements

This work was supported by the M4 Award 2011 from the Bayrisches Staatsministerium für Wirtschaft, Infrastruktur Verkehr und Technologie (to F.H.). We thank A. Vogel, S. Giusti, D. Refojo (Max Planck Institute of Psychiatry) and M. Baumann (Lead Discovery Center) for experimental advice and L. Tietze, T. Gerlach and B. Hoogeland for technical support. We are indebted to E. Weyher (Max Planck Institute of Biochemistry) and to C. Dubler (Ludwig-Maximilians-University Munich) for high-resolution MS and NMR measurements. We thank S. Ley for a sample of antascomycin B (University of Cambridge, UK); the Joint Structural Biology Group staff at the European Synchrotron Radiation Facility in Grenoble, France; the staff at beamline X10SA of the Swiss Synchrotron Light Source (SLS) in Villigen, Switzerland; and F. Holsboer for continuous support.

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Author notes

  1. Christian Kozany

    Present address: Present address: Sequiserve, Vaterstetten, Germany.,

  2. Steffen Gaali and Alexander Kirschner: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

    Steffen Gaali, Alexander Kirschner, Serena Cuboni, Christian Kozany, Christian Namendorf, Claudia Sippel, Anthony S Zannas, Elisabeth B Binder, Manfred Uhr & Felix Hausch

  2. Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany

    Jakob Hartmann, Georgia Balsevich, Paula Fernandez-Vizarra, Osborne F X Almeida, Mathias V Schmidt & Chadi Touma

  3. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA

    Anthony S Zannas

  4. Medizinische Klinik und Poliklinik IV, Hospital of the University of Munich, Munich, Germany

    Rika Draenert

  5. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA

    Elisabeth B Binder

  6. Lead Discovery Center GmbH, Dortmund, Germany

    Gerd Rühter

  7. Max Planck Institute of Biochemistry, Martinsried, Germany

    Andreas Bracher

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Contributions

F.H. conceived the project; S.G. designed and synthesized FKBP ligands; G.R. contributed to the design of ligand 1, iFit 4 and SAFit2; A.K. and S.C. performed neurite outgrowth experiments; C.K. and C.S. performed FKBP binding assays; P.F.-V. and O.X.F.A. supported primary neuron experiments; C.N. and M.U. measured PK parameters; A.B. performed crystallographic analyses; J.H., G.B., M.V.S. and C.T. performed animal behavioral testing. A.S.Z., R.D. and E.B.B. designed and performed the immune experiments. S.G., A.K., P.F.-V., O.X.F.A., A.B. and F.H. wrote the manuscript.

Corresponding author

Correspondence to Felix Hausch.

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Competing interests

Declaration: A.K., S.G., G.R., A.B. and F.H. have filed a patent application for selective FKBP51 inhibitors (EP 13185247). E.B. is co-inventor on European Patent no. EP 1687443 B1, 'FKBP5: a novel target for antidepressant therapy'.

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Gaali, S., Kirschner, A., Cuboni, S. et al. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol 11, 33–37 (2015). https://doi.org/10.1038/nchembio.1699

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