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Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt
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 relati...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430017/ https://www.ncbi.nlm.nih.gov/pubmed/30996949 http://dx.doi.org/10.1039/c8sc05212c |
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author | Uhlenbrock, Niklas Smith, Steven Weisner, Jörn Landel, Ina Lindemann, Marius Le, Thien Anh Hardick, Julia Gontla, Rajesh Scheinpflug, Rebekka Czodrowski, Paul Janning, Petra Depta, Laura Quambusch, Lena Müller, Matthias P. Engels, Bernd Rauh, Daniel |
author_facet | Uhlenbrock, Niklas Smith, Steven Weisner, Jörn Landel, Ina Lindemann, Marius Le, Thien Anh Hardick, Julia Gontla, Rajesh Scheinpflug, Rebekka Czodrowski, Paul Janning, Petra Depta, Laura Quambusch, Lena Müller, Matthias P. Engels, Bernd Rauh, Daniel |
author_sort | Uhlenbrock, Niklas |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6430017 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-64300172019-04-17 Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt Uhlenbrock, Niklas Smith, Steven Weisner, Jörn Landel, Ina Lindemann, Marius Le, Thien Anh Hardick, Julia Gontla, Rajesh Scheinpflug, Rebekka Czodrowski, Paul Janning, Petra Depta, Laura Quambusch, Lena Müller, Matthias P. Engels, Bernd Rauh, Daniel Chem Sci Chemistry 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. Royal Society of Chemistry 2019-02-13 /pmc/articles/PMC6430017/ /pubmed/30996949 http://dx.doi.org/10.1039/c8sc05212c Text en This journal is © The Royal Society of Chemistry 2019 http://creativecommons.org/licenses/by/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0) |
spellingShingle | Chemistry Uhlenbrock, Niklas Smith, Steven Weisner, Jörn Landel, Ina Lindemann, Marius Le, Thien Anh Hardick, Julia Gontla, Rajesh Scheinpflug, Rebekka Czodrowski, Paul Janning, Petra Depta, Laura Quambusch, Lena Müller, Matthias P. Engels, Bernd Rauh, Daniel Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt |
title | Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt
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title_full | Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt
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title_fullStr | Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt
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title_full_unstemmed | Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt
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title_short | Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt
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title_sort | structural and chemical insights into the covalent-allosteric inhibition of the protein kinase akt |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430017/ https://www.ncbi.nlm.nih.gov/pubmed/30996949 http://dx.doi.org/10.1039/c8sc05212c |
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