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| Status |
Public on Jul 18, 2017 |
| Title |
Genome-wide inhibition of pro-atherogenic gene expression by multi-STAT targeting compounds as a novel treatment strategy of CVD |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Cardiovascular diseases (CVD), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis and plaque development include the pro-infslammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of members of the Signal Transducer and Activator of Transcription (STAT) family. Searches for STAT3-targeting compounds, exploring the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT-specific. We hypothesized that non-specific STAT-inhibitors that simultaneously block STAT1, STAT2 and STAT3 activity and pro-inflammatory target gene expression may be a promising avenue for the treatment of CVD. We developed a pipeline approach combining comparative in silico docking of multiple STAT-SH2 models on multi-million Clean Lead and Clean Drug-Like libraries with in vitro STAT inhibition validation, as a novel STAT-inhibitory selection strategy. This approach allowed us to identify a new type of non-specific STAT inhibitor, C01L_F03 targeting the SH2 domain of STAT1, 2 and 3 with equal affinity. Moreover we observed a similar STAT cross-binding mechanism for STATTIC and STX-0119, leading to genome-wide inhibition of pro-atherogenic gene expression. Consequently, a multi-STAT inhibitory strategy was applied to inhibit endothelial cell (EC) migration, leukocyte adhesion to ECs and impairment of aortic ring contractility under inflammatory conditions. Together, this implicates that multi-STAT inhibition could provide a powerfull approach for the success of combating vascular inflammation in CVD
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| Overall design |
RNA obtained from HMEC treated with inhibitory compounds and IFNγ+LPS was compared to RNA isolated from untreated HMEC.
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| Contributor(s) |
Plens-Galaska M, Szelag M, Colladoc A, Marquesc P, Vallejoe S, Ramos-Gonzáleze M, Wesoly J, Sanz MJ, Peiró C, Bluyssen HA |
| Citation(s) |
30283459 |
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| Submission date |
Jul 17, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Martyna Plens Gałąska |
| E-mail(s) |
martyna.plens-galaska@amu.edu.pl
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| Organization name |
Adam Mickiewicz Univerity
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| Department |
Human Molecular Genetics
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| Street address |
Umultowska 89
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| City |
Poznan |
| State/province |
Wielkopolska |
| ZIP/Postal code |
61-614 |
| Country |
Poland |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA394705 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE101508_RAW.tar |
26.2 Mb |
(http)(custom) |
TAR |
| GSE101508_non-normalized_data.txt.gz |
3.2 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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