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
  • 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.