Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt.
Journal
Chemical science
ISSN: 2041-6520
Titre abrégé: Chem Sci
Pays: England
ID NLM: 101545951
Informations de publication
Date de publication:
28 Mar 2019
28 Mar 2019
Historique:
received:
22
11
2018
accepted:
12
02
2019
entrez:
19
4
2019
pubmed:
19
4
2019
medline:
19
4
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30996949
doi: 10.1039/c8sc05212c
pii: c8sc05212c
pmc: PMC6430017
doi:
Types de publication
Journal Article
Langues
eng
Pagination
3573-3585Références
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