Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstaclesReport as inadecuate




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Cell Regeneration

, 4:2

First Online: 12 March 2015Received: 04 November 2014Accepted: 10 February 2015DOI: 10.1186-s13619-015-0015-x

Cite this article as: Fontaine, F., Overman, J. & François, M. Cell Regen 2015 4: 2. doi:10.1186-s13619-015-0015-x

Abstract

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.

KeywordsTranscription Screening Proteomics Interactome Pharmacology Specificity Cancer Genomics AbbreviationsPPIDProtein-protein interaction disruptor

TFTranscription factor

HMGHigh-mobility group

ChIP-seqChromatin immunoprecipitation sequencing

GPCRG protein-coupled receptors

RIMERapid immunoprecipitation mass spectrometry of endogenous proteins

NSAIDNonsteroidal anti-inflammatory drug

AP-MSAffinity purification-mass spectrometry

RNA-seqRNA-sequencing

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Author: Frank Fontaine - Jeroen Overman - Mathias François

Source: https://link.springer.com/







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