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The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design

The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitor...

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Autores principales: Couty, Sylvain, Westwood, Isaac M., Kalusa, Andrew, Cano, Celine, Travers, Jon, Boxall, Kathy, Chow, Chiau Ling, Burns, Sam, Schmitt, Jessica, Pickard, Lisa, Barillari, Caterina, McAndrew, P. Craig, Clarke, Paul A., Linardopoulos, Spiros, Griffin, Roger J., Aherne, G. Wynne, Raynaud, Florence I., Workman, Paul, Jones, Keith, van Montfort, Rob L.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858552/
https://www.ncbi.nlm.nih.gov/pubmed/24072592
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author Couty, Sylvain
Westwood, Isaac M.
Kalusa, Andrew
Cano, Celine
Travers, Jon
Boxall, Kathy
Chow, Chiau Ling
Burns, Sam
Schmitt, Jessica
Pickard, Lisa
Barillari, Caterina
McAndrew, P. Craig
Clarke, Paul A.
Linardopoulos, Spiros
Griffin, Roger J.
Aherne, G. Wynne
Raynaud, Florence I.
Workman, Paul
Jones, Keith
van Montfort, Rob L.M.
author_facet Couty, Sylvain
Westwood, Isaac M.
Kalusa, Andrew
Cano, Celine
Travers, Jon
Boxall, Kathy
Chow, Chiau Ling
Burns, Sam
Schmitt, Jessica
Pickard, Lisa
Barillari, Caterina
McAndrew, P. Craig
Clarke, Paul A.
Linardopoulos, Spiros
Griffin, Roger J.
Aherne, G. Wynne
Raynaud, Florence I.
Workman, Paul
Jones, Keith
van Montfort, Rob L.M.
author_sort Couty, Sylvain
collection PubMed
description The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases.
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spelling pubmed-38585522013-12-11 The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design Couty, Sylvain Westwood, Isaac M. Kalusa, Andrew Cano, Celine Travers, Jon Boxall, Kathy Chow, Chiau Ling Burns, Sam Schmitt, Jessica Pickard, Lisa Barillari, Caterina McAndrew, P. Craig Clarke, Paul A. Linardopoulos, Spiros Griffin, Roger J. Aherne, G. Wynne Raynaud, Florence I. Workman, Paul Jones, Keith van Montfort, Rob L.M. Oncotarget Research Paper The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases. Impact Journals LLC 2013-08-25 /pmc/articles/PMC3858552/ /pubmed/24072592 Text en Copyright: © 2013 Couty et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
spellingShingle Research Paper
Couty, Sylvain
Westwood, Isaac M.
Kalusa, Andrew
Cano, Celine
Travers, Jon
Boxall, Kathy
Chow, Chiau Ling
Burns, Sam
Schmitt, Jessica
Pickard, Lisa
Barillari, Caterina
McAndrew, P. Craig
Clarke, Paul A.
Linardopoulos, Spiros
Griffin, Roger J.
Aherne, G. Wynne
Raynaud, Florence I.
Workman, Paul
Jones, Keith
van Montfort, Rob L.M.
The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design
title The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design
title_full The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design
title_fullStr The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design
title_full_unstemmed The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design
title_short The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design
title_sort discovery of potent ribosomal s6 kinase inhibitors by high-throughput screening and structure-guided drug design
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858552/
https://www.ncbi.nlm.nih.gov/pubmed/24072592
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