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Issue 12, 2019
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Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt

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Abstract

The Ser/Thr kinase Akt (Protein Kinase B/PKB) is a master switch in cellular signal transduction pathways. Its downstream signaling influences cell proliferation, cell growth, and apoptosis, rendering Akt a prominent drug target. The unique activation mechanism of Akt involves a change of the relative orientation of its N-terminal pleckstrin homology (PH) and the kinase domain and makes this kinase suitable for highly specific allosteric modulation. Here we present a unique set of crystal structures of covalent-allosteric interdomain inhibitors in complex with full-length Akt and report the structure-based design, synthesis, biological and pharmacological evaluation of a focused library of these innovative inhibitors.

Graphical abstract: Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt

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Publication details

The article was received on 22 Nov 2018, accepted on 12 Feb 2019 and first published on 13 Feb 2019


Article type: Edge Article
DOI: 10.1039/C8SC05212C
Citation: Chem. Sci., 2019,10, 3573-3585
  • Open access: Creative Commons BY license
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    Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt

    N. Uhlenbrock, S. Smith, J. Weisner, I. Landel, M. Lindemann, T. A. Le, J. Hardick, R. Gontla, R. Scheinpflug, P. Czodrowski, P. Janning, L. Depta, L. Quambusch, M. P. Müller, B. Engels and D. Rauh, Chem. Sci., 2019, 10, 3573
    DOI: 10.1039/C8SC05212C

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