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

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Niklas Uhlenbrock
  • Steven Smith
  • Joern Weisner
  • Ina Landel
  • Marius Lindemann
  • Thien Anh Le
  • Julia Hardick
  • Rajesh Gontla
  • Rebekka Scheinpflug
  • Paul Czodrowski
  • Petra Janning
  • Laura Depta
  • Lena Quambusch
  • Matthias P Mueller
  • Bernd Engels
  • Daniel Rauh
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000463759100012&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1039/c8sc05212c
eISSN
2041-6539
Externe Identifier
  • Clarivate Analytics Document Solution ID: HS3JP
  • PubMed Identifier: 30996949
ISSN
2041-6520
Ausgabe der Veröffentlichung
12
Zeitschrift
CHEMICAL SCIENCE
Paginierung
3573 - 3585
Datum der Veröffentlichung
2019
Status
Published
Titel
Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt
Sub types
  • Article
Ausgabe der Zeitschrift
10

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Abstract
<p>Structure-based driven synthesis and biological evaluation provide innovative novel covalent-allosteric Akt inhibitors.</p>
Autoren
  • 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
  • Daniel Rauh
DOI
10.1039/c8sc05212c
eISSN
2041-6539
ISSN
2041-6520
Ausgabe der Veröffentlichung
12
Zeitschrift
Chemical Science
Sprache
en
Online publication date
2019
Paginierung
3573 - 3585
Status
Published online
Herausgeber
Royal Society of Chemistry (RSC)
Herausgeber URL
http://dx.doi.org/10.1039/c8sc05212c
Datum der Datenerfassung
2024
Titel
Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt
Ausgabe der Zeitschrift
10

Datenquelle: Crossref

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.
Addresses
  • 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: daniel.rauh@tu-dortmund.de ; http://www.ddhdortmund.de ; www.twitter.com/DDHDortmund.
Autoren
  • 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
  • Daniel Rauh
DOI
10.1039/c8sc05212c
eISSN
2041-6539
Externe Identifier
  • PubMed Identifier: 30996949
  • PubMed Central ID: PMC6430017
Funding acknowledgements
  • Bundesministerium für Bildung und Forschung: BMBF 01GS08104, 01ZX1303C
  • European Regional Development Fund: EFRE-800400
  • Deutsche Forschungsgemeinschaft:
Open access
true
ISSN
2041-6520
Ausgabe der Veröffentlichung
12
Zeitschrift
Chemical science
Sprache
eng
Medium
Electronic-eCollection
Online publication date
2019
Open access status
Open Access
Paginierung
3573 - 3585
Datum der Veröffentlichung
2019
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2019
Titel
Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
10

Files

https://pubs.rsc.org/en/content/articlepdf/2019/sc/c8sc05212c https://europepmc.org/articles/PMC6430017?pdf=render

Datenquelle: Europe PubMed Central

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.
Date of acceptance
2019
Autoren
  • 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
  • Daniel Rauh
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/30996949
DOI
10.1039/c8sc05212c
Externe Identifier
  • PubMed Central ID: PMC6430017
ISSN
2041-6520
Ausgabe der Veröffentlichung
12
Zeitschrift
Chem Sci
Sprache
eng
Country
England
Paginierung
3573 - 3585
PII
c8sc05212c
Datum der Veröffentlichung
2019
Status
Published online
Titel
Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
10

Datenquelle: PubMed

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