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

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.

SUBMITTER: Uhlenbrock N

PROVIDER: S-EPMC6430017 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Uhlenbrock Niklas N Smith Steven S Weisner Jörn J Landel Ina I Lindemann Marius M Le Thien Anh TA Hardick Julia J Gontla Rajesh R Scheinpflug Rebekka R Czodrowski Paul P Janning Petra P Depta Laura L Quambusch Lena L Müller Matthias P MP Engels Bernd B Rauh Daniel D

Chemical science 20190213 12

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 struct ...[more]

PMID: 30996949

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