Targeted inhibition of STATs and IRFs as a potential treatment strategy in cardiovascular disease
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Malgorzata Szelag1, Anna Piaszyk-Borychowska1, Martyna Plens-Galaska1, Joanna Wesoly2 and Hans A.R. Bluyssen1
1 Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
2 Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
Hans A.R. Bluyssen, email:
Keywords: STAT, IRF, vascular inflammation, in silico modeling, therapeutic strategy
Received: December 08, 2015 Accepted: April 22, 2016 Published: May 05, 2016
Key factors contributing to early stages of atherosclerosis and plaque development include the pro-inflammatory cytokines Interferon (IFN)α, IFNγ and Interleukin (IL)-6 and Toll-like receptor 4 (TLR4) stimuli. Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT) and Interferon Regulatory Factor (IRF) families. In particular, STAT1, 2 and 3; IRF1 and 8 have recently been recognized as prominent modulators of inflammation, especially in immune and vascular cells during atherosclerosis. Moreover, inflammation-mediated activation of these STATs and IRFs coordinates a platform for synergistic amplification leading to pro-atherogenic responses.
Searches for STAT3-targeting compounds, exploring the pTyr-SH2 interaction area of STAT3, yielded many small molecules including natural products. Only a few inhibitors for other STATs, but none for IRFs, are described. Promising results for several STAT3 inhibitors in recent clinical trials predicts STAT3-inhibiting strategies may find their way to the clinic. However, many of these inhibitors do not seem STAT-specific, display toxicity and are not very potent. This illustrates the need for better models, and screening and validation tools for novel STAT and IRF inhibitors.
This review presents a summary of these findings. It postulates STAT1, STAT2 and STAT3 and IRF1 and IRF8 as interesting therapeutic targets and targeted inhibition could be a potential treatment strategy in CVDs. In addition, it proposes a pipeline approach that combines comparative in silico docking of STAT-SH2 and IRF-DBD models with in vitro STAT and IRF activation inhibition validation, as a novel tool to screen multi-million compound libraries and identify specific inhibitors for STATs and IRFs.
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