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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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Supplementary files

Article information


Submitted
22 Nov 2018
Accepted
12 Feb 2019
First published
13 Feb 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2019,10, 3573-3585
Article type
Edge Article

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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