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Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9
Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenot...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048338/ https://www.ncbi.nlm.nih.gov/pubmed/27746890 http://dx.doi.org/10.1039/c6md00159a |
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author | Rye, Carl S. Chessum, Nicola E. A. Lamont, Scott Pike, Kurt G. Faulder, Paul Demeritt, Julie Kemmitt, Paul Tucker, Julie Zani, Lorenzo Cheeseman, Matthew D. Isaac, Rosie Goodwin, Louise Boros, Joanna Raynaud, Florence Hayes, Angela Henley, Alan T. de Billy, Emmanuel Lynch, Christopher J. Sharp, Swee Y. te Poele, Robert Fee, Lisa O’ Foote, Kevin M. Green, Stephen Workman, Paul Jones, Keith |
author_facet | Rye, Carl S. Chessum, Nicola E. A. Lamont, Scott Pike, Kurt G. Faulder, Paul Demeritt, Julie Kemmitt, Paul Tucker, Julie Zani, Lorenzo Cheeseman, Matthew D. Isaac, Rosie Goodwin, Louise Boros, Joanna Raynaud, Florence Hayes, Angela Henley, Alan T. de Billy, Emmanuel Lynch, Christopher J. Sharp, Swee Y. te Poele, Robert Fee, Lisa O’ Foote, Kevin M. Green, Stephen Workman, Paul Jones, Keith |
author_sort | Rye, Carl S. |
collection | PubMed |
description | Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine 25 was also shown to have high potency against the CDK9 enzyme (3 nM). |
format | Online Article Text |
id | pubmed-5048338 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-50483382016-10-12 Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9 Rye, Carl S. Chessum, Nicola E. A. Lamont, Scott Pike, Kurt G. Faulder, Paul Demeritt, Julie Kemmitt, Paul Tucker, Julie Zani, Lorenzo Cheeseman, Matthew D. Isaac, Rosie Goodwin, Louise Boros, Joanna Raynaud, Florence Hayes, Angela Henley, Alan T. de Billy, Emmanuel Lynch, Christopher J. Sharp, Swee Y. te Poele, Robert Fee, Lisa O’ Foote, Kevin M. Green, Stephen Workman, Paul Jones, Keith Medchemcomm Chemistry Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine 25 was also shown to have high potency against the CDK9 enzyme (3 nM). Royal Society of Chemistry 2016-08-01 2016-06-13 /pmc/articles/PMC5048338/ /pubmed/27746890 http://dx.doi.org/10.1039/c6md00159a Text en This journal is © The Royal Society of Chemistry 2016 http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Chemistry Rye, Carl S. Chessum, Nicola E. A. Lamont, Scott Pike, Kurt G. Faulder, Paul Demeritt, Julie Kemmitt, Paul Tucker, Julie Zani, Lorenzo Cheeseman, Matthew D. Isaac, Rosie Goodwin, Louise Boros, Joanna Raynaud, Florence Hayes, Angela Henley, Alan T. de Billy, Emmanuel Lynch, Christopher J. Sharp, Swee Y. te Poele, Robert Fee, Lisa O’ Foote, Kevin M. Green, Stephen Workman, Paul Jones, Keith Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9 |
title | Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9
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title_full | Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9
|
title_fullStr | Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9
|
title_full_unstemmed | Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9
|
title_short | Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9
|
title_sort | discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (hsf1) stress pathway and cdk9 |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048338/ https://www.ncbi.nlm.nih.gov/pubmed/27746890 http://dx.doi.org/10.1039/c6md00159a |
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