Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors
BACKGROUND: SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology. However, rationally engineering specific inhibitors that interfere with transcription factor DN...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Chinese Society for Cell Biology
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306199/ https://www.ncbi.nlm.nih.gov/pubmed/25678957 http://dx.doi.org/10.1186/2045-9769-3-10 |
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author | Narasimhan, Kamesh Micoine, Kevin Lacôte, Emmanuel Thorimbert, Serge Cheung, Edwin Hasenknopf, Bernold Jauch, Ralf |
author_facet | Narasimhan, Kamesh Micoine, Kevin Lacôte, Emmanuel Thorimbert, Serge Cheung, Edwin Hasenknopf, Bernold Jauch, Ralf |
author_sort | Narasimhan, Kamesh |
collection | PubMed |
description | BACKGROUND: SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology. However, rationally engineering specific inhibitors that interfere with transcription factor DNA interfaces continues to be a monumental challenge in the field of transcription factor chemical biology. Polyoxometalates (POMs) are inorganic compounds that were previously shown to target the high-mobility group (HMG) of SOX proteins at nanomolar concentrations. In continuation of this work, we carried out an assessment of the selectivity of a panel of newly synthesized organo-polyoxometalate hybrids in targeting different transcription factor families to enable the usage of polyoxometalates as specific SOX transcription factor drugs. RESULTS: The residual DNA-binding activities of 15 different transcription factors were measured after treatment with a panel of diverse polyoxometalates. Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class. Further, organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity. The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency. CONCLUSION: Polyoxometalates are highly potent, nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family. However, binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families. Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR. In summary, our report reaffirms that transcription factors are challenging molecular architectures and that future polyoxometalate chemistry must consider further modification strategies, to address the substantial challenges involved in achieving target selectivity. |
format | Online Article Text |
id | pubmed-4306199 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Chinese Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-43061992015-02-12 Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors Narasimhan, Kamesh Micoine, Kevin Lacôte, Emmanuel Thorimbert, Serge Cheung, Edwin Hasenknopf, Bernold Jauch, Ralf Cell Regen Short Report BACKGROUND: SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology. However, rationally engineering specific inhibitors that interfere with transcription factor DNA interfaces continues to be a monumental challenge in the field of transcription factor chemical biology. Polyoxometalates (POMs) are inorganic compounds that were previously shown to target the high-mobility group (HMG) of SOX proteins at nanomolar concentrations. In continuation of this work, we carried out an assessment of the selectivity of a panel of newly synthesized organo-polyoxometalate hybrids in targeting different transcription factor families to enable the usage of polyoxometalates as specific SOX transcription factor drugs. RESULTS: The residual DNA-binding activities of 15 different transcription factors were measured after treatment with a panel of diverse polyoxometalates. Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class. Further, organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity. The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency. CONCLUSION: Polyoxometalates are highly potent, nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family. However, binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families. Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR. In summary, our report reaffirms that transcription factors are challenging molecular architectures and that future polyoxometalate chemistry must consider further modification strategies, to address the substantial challenges involved in achieving target selectivity. Chinese Society for Cell Biology 2014-07-19 /pmc/articles/PMC4306199/ /pubmed/25678957 http://dx.doi.org/10.1186/2045-9769-3-10 Text en Copyright © 2014 Narasimhan et al.; licensee BioMed Central Ltd. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0 (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Short Report Narasimhan, Kamesh Micoine, Kevin Lacôte, Emmanuel Thorimbert, Serge Cheung, Edwin Hasenknopf, Bernold Jauch, Ralf Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors |
title | Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors |
title_full | Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors |
title_fullStr | Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors |
title_full_unstemmed | Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors |
title_short | Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors |
title_sort | exploring the utility of organo-polyoxometalate hybrids to inhibit sox transcription factors |
topic | Short Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306199/ https://www.ncbi.nlm.nih.gov/pubmed/25678957 http://dx.doi.org/10.1186/2045-9769-3-10 |
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