2. Academic Validation
  3. Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt

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

  • Chem Sci. 2019 Feb 13;10(12):3573-3585. doi: 10.1039/c8sc05212c.
Niklas Uhlenbrock 1,  Steven Smith 1,  Jörn Weisner 1,  Ina Landel 1,  Marius Lindemann 1,  Thien Anh Le 2,  Julia Hardick 1,  Rajesh Gontla 1,  Rebekka Scheinpflug 1,  Paul Czodrowski 1,  Petra Janning 3,  Laura Depta 1,  Lena Quambusch 1,  Matthias P Müller 1,  Bernd Engels 2,  Daniel Rauh 1
Affiliations

Affiliations

  • 1 Faculty of Chemistry and Chemical Biology , TU Dortmund University , Drug Discovery Hub Dortmund (DDHD) am Zentrum für integrierte Wirkstoffforschung (ZIW) , Otto-Hahn-Strasse 4a , 44227 Dortmund , Germany . Email: [email protected] ; http://www.ddhdortmund.de ; www.twitter.com/DDHDortmund.
  • 2 Faculty for Chemistry and Pharmacy , Institut für Physikalische und Theoretische Chemie , Universität Würzburg , Emil-Fischer-Strasse 42 , 97074 Würzburg , Germany.
  • 3 Max-Planck-Institut für Molekulare Physiologie , Abteilung Chemische Biologie , Otto-Hahn-Strasse 11 , 44227 Dortmund , Germany.
PMID: 30996949 DOI: 10.1039/c8sc05212c
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.

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