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Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles

Much research on transcription factor biology and their genetic pathways has been undertaken over the last 30 years, especially in the field of developmental biology and cancer. Yet, very little is known about the molecular modalities of highly dynamic interactions between transcription factors, gen...

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Autores principales: Fontaine, Frank, Overman, Jeroen, François, Mathias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365538/
https://www.ncbi.nlm.nih.gov/pubmed/25848531
http://dx.doi.org/10.1186/s13619-015-0015-x
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author Fontaine, Frank
Overman, Jeroen
François, Mathias
author_facet Fontaine, Frank
Overman, Jeroen
François, Mathias
author_sort Fontaine, Frank
collection PubMed
description Much research on transcription factor biology and their genetic pathways has been undertaken over the last 30 years, especially in the field of developmental biology and cancer. Yet, very little is known about the molecular modalities of highly dynamic interactions between transcription factors, genomic DNA, and protein partners. Methodological breakthroughs such as RNA-seq (RNA-sequencing), ChIP-seq (chromatin immunoprecipitation sequencing), RIME (rapid immunoprecipitation mass spectrometry of endogenous proteins), and single-molecule imaging will dramatically accelerate the discovery rate of their molecular mode of action in the next few years. From a pharmacological viewpoint, conventional methods used to target transcription factor activity with molecules mimicking endogenous ligands fail to achieve high specificity and are limited by a lack of identification of new molecular targets. Protein-protein interactions are likely to represent one of the next major classes of therapeutic targets. Transcription factors, known to act mostly via protein-protein interaction, may well be at the forefront of this type of drug development. One hurdle in this field remains the difficulty to collate structural data into meaningful information for rational drug design. Another hurdle is the lack of chemical libraries meeting the structural requirements of protein-protein interaction disruption. As more attempts at modulating transcription factor activity are undertaken, valuable knowledge will be accumulated on the modality of action required to modulate transcription and how these findings can be applied to developing transcription factor drugs. Key discoveries will spawn into new therapeutic approaches not only as anticancer targets but also for other indications, such as those with an inflammatory component including neurodegenerative disorders, diabetes, and chronic liver and kidney diseases.
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spelling pubmed-43655382015-04-06 Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles Fontaine, Frank Overman, Jeroen François, Mathias Cell Regen Review Much research on transcription factor biology and their genetic pathways has been undertaken over the last 30 years, especially in the field of developmental biology and cancer. Yet, very little is known about the molecular modalities of highly dynamic interactions between transcription factors, genomic DNA, and protein partners. Methodological breakthroughs such as RNA-seq (RNA-sequencing), ChIP-seq (chromatin immunoprecipitation sequencing), RIME (rapid immunoprecipitation mass spectrometry of endogenous proteins), and single-molecule imaging will dramatically accelerate the discovery rate of their molecular mode of action in the next few years. From a pharmacological viewpoint, conventional methods used to target transcription factor activity with molecules mimicking endogenous ligands fail to achieve high specificity and are limited by a lack of identification of new molecular targets. Protein-protein interactions are likely to represent one of the next major classes of therapeutic targets. Transcription factors, known to act mostly via protein-protein interaction, may well be at the forefront of this type of drug development. One hurdle in this field remains the difficulty to collate structural data into meaningful information for rational drug design. Another hurdle is the lack of chemical libraries meeting the structural requirements of protein-protein interaction disruption. As more attempts at modulating transcription factor activity are undertaken, valuable knowledge will be accumulated on the modality of action required to modulate transcription and how these findings can be applied to developing transcription factor drugs. Key discoveries will spawn into new therapeutic approaches not only as anticancer targets but also for other indications, such as those with an inflammatory component including neurodegenerative disorders, diabetes, and chronic liver and kidney diseases. BioMed Central 2015-03-12 /pmc/articles/PMC4365538/ /pubmed/25848531 http://dx.doi.org/10.1186/s13619-015-0015-x Text en © Fontaine et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://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/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Review
Fontaine, Frank
Overman, Jeroen
François, Mathias
Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles
title Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles
title_full Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles
title_fullStr Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles
title_full_unstemmed Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles
title_short Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles
title_sort pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365538/
https://www.ncbi.nlm.nih.gov/pubmed/25848531
http://dx.doi.org/10.1186/s13619-015-0015-x
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