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An Optimised Small-Molecule Stabiliser of the 14-3-3–PMA2 Protein–Protein Interaction

Authors

  • Dr. Anja Richter,

    1. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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    • These authors contributed equally to this work.

  • Dr. Rolf Rose,

    1. Chemical Genomics Centre of the Max-Planck-Society, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany)
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    • These authors contributed equally to this work.

  • Dr. Christian Hedberg,

    1. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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  • Prof. Dr. Herbert Waldmann,

    Corresponding author
    1. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Fakultät Chemie, Fachbereich Chemische Biologie, Technische Universität Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
    • Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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  • Dr. Christian Ottmann

    Corresponding author
    1. Chemical Genomics Centre of the Max-Planck-Society, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany)
    • Chemical Genomics Centre of the Max-Planck-Society, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany)
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Abstract

Modulation of protein–protein interactions (PPIs) is a highly demanding, but also a very promising approach in chemical biology and targeted drug discovery. In contrast to inhibiting PPIs with small, chemically tractable molecules, stabilisation of these interactions can only be achieved with complex natural products, like rapamycin, FK506, taxol, forskolin, brefeldin and fusicoccin. Fusicoccin stabilises the activatory complex of the plant H+-ATPase PMA2 and 14-3-3 proteins. Recently, we have shown that the stabilising effect of fusicoccin could be mimicked by a trisubstituted pyrrolinone (pyrrolidone1, 1). Here, we report the synthesis, functional activity and crystal structure of derivatives of 1 that stabilise the 14-3-3–PMA2 complex. With a limited compound collection three modifications that are important for activity enhancement could be determined: 1) conversion of the pyrrolinone scaffold into a pyrazole, 2) introduction of a tetrazole moiety to the phenyl ring that contacts PMA2, and 3) addition of a bromine to the phenyl ring that exclusively contacts the 14-3-3 protein. The crystal structure of a pyrazole derivative of 1 in complex with 14-3-3 and PMA2 revealed that the more rigid core of this molecule positions the stabiliser deeper into the rim of the interface, enlarging especially the contact surface to PMA2. Combination of the aforementioned features gave rise to a molecule (37) that displays a threefold increase in stabilising the 14-3-3–PMA2 complex over 1. Compound 37 and the other active derivatives show no effect on two other important 14-3-3 protein–protein interactions, that is, with CRaf and p53. This is the first study that describes the successful optimisation of a PPI stabiliser identified by screening.

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