Structural and Chemical Insights into the Covalent-allosteric Inhibition of the Protein Kinase Akt

Niklas Uhlenbrock, Steven Smith, Jörn Weisner, Ina Landel, Marius Lindemann, Thien Anh Le, Julia Hardick, Rajesh Gontla, Rebekka Scheinpflug, Paul Czodrowski, Petra Janning, Laura Depta, Lena Quambusch, Matthias P. Müller, Bernd Engels and Daniel Rauh

The Ser/Thr Kinase Akt (Protein Kinase B/PKB) is a master switch in cellular signal transduction pathways. Ist 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 structurebased design, synthesis, biological and pharmacological evaluation of a focused library of these innovative inhibitors.

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