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3,5-Diphenylpent-2-enoic Acids as Allosteric Activators of the Protein Kinase PDK1: Structure−Activity Relationships and Thermodynamic Characterization of Binding as Paradigms for PIF-Binding Pocket-Targeting Compounds†

PDB code of 2Z with PDK1: 3HRF.

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    3,5-Diphenylpent-2-enoic Acids as Allosteric Activators of the Protein Kinase PDK1: Structure−Activity Relationships and Thermodynamic Characterization of Binding as Paradigms for PIF-Binding Pocket-Targeting Compounds†
    †

    PDB code of 2Z with PDK1: 3HRF.

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    ‡ Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbrücken, Germany
    § Unité de Biochimie Structurale (CNRS-URA 2185), Institut Pasteur, F-75724 Paris, France
    ∥ Department of Internal Medicine I, University of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt a.M., Germany
    *To whom correspondence should be addressed. Phone: +49 681 302 70312. Fax: +49 681 302 70308. E-mail: [email protected]. Web site: http://www.pharmmedchem.de.
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2009, 52, 15, 4683–4693
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    https://doi.org/10.1021/jm9001499
    Published July 17, 2009
    Copyright © 2009 American Chemical Society
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    Abstract

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    The modulation of protein kinase activities by low molecular weight compounds is a major goal of current pharmaceutical developments. In this line, important efforts are directed to the development of drugs targeting the conserved ATP binding site. However, there is very little experience on targeting allosteric, regulatory sites, different from the ATP binding site, in protein kinases. Here we describe the synthesis, cell-free activation potency, and calorimetric binding analysis of 3,5-diphenylpent-2-enoic acids and derivatives as allosteric modulators of the phosphoinositide-dependent kinase-1 (PDK1) catalytic activity. Our SAR results combined with thermodynamic binding analyses revealed both favorable binding enthalpy and entropy and confirmed the PIF-binding pocket of PDK1 as a druggable site. In conclusion, we defined the minimal structural requirements for compounds to bind to the PIF-binding pocket and to act as allosteric modulators and identified two new lead structures (12Z and 13Z) with predominating binding enthalpy.

    Copyright © 2009 American Chemical Society

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    Synthetic procedures and NMR spectroscopic data of compounds 2c−14c, 21c, 2b−13b, 15b−18b, 21b, 2a−20a, 21Ea, 3−5Z, 9−11Z, 14−15Z, 18Z, 3−11E, 13−14E, 18E, 16−17E/Z, 19, 20, 21; 2D-NOESY−1H NMR spectroscopic data on 2Z/2E. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2009, 52, 15, 4683–4693
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    https://doi.org/10.1021/jm9001499
    Published July 17, 2009
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