Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs

Abstract

Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT)s. Searches for compounds targeting the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT3-specific. We hypothesized that multi-STAT-inhibitors that simultaneously block STAT1, STAT2, and STAT3 activity and pro-inflammatory target gene expression may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple STAT-SH2 models on multi-million compound libraries, we identified the novel multi-STAT inhibitor, C01L_F03. This compound targets the SH2 domain of STAT1, STAT2, and STAT3 with the same affinity and simultaneously blocks their activity and expression of multiple STAT-target genes in HMECs in response to IFNα. The same in silico and in vitro multi-STAT inhibiting capacity was shown for STATTIC and STX-0119. Moreover, C01L_F03, STATTIC and STX-0119 were also able to affect genome-wide interactions between IFNγ and TLR4 by commonly inhibiting pro-inflammatory and pro-atherogenic gene expression directed by cooperative involvement of STATs with IRFs and/or NF-κB. Moreover, we observed that multi-STAT inhibitors could be used to inhibit IFNγ+LPS-induced HMECs migration, leukocyte adhesion to ECs as well as impairment of mesenteric artery contractility. Together, this implicates that application of a multi-STAT inhibitory strategy could provide great promise for the treatment of CVDs.

Direct Inhibition of IRF-Dependent Transcriptional Regulatory Mechanisms Associated With Disease

“…Analysis of the corresponding total binding score values (BS) and CBAVs of STATTIC and STX-0119 calculated for each individual STAT, points to their equal binding affinities for STAT1, STAT2, and STAT3 (222). In the same study, we described a novel pan-STAT1/2/3 inhibitor, C01L_F03, with similar characteristics (225). We proposed that this novel class of inhibitors could be implemented in a multi-STAT inhibitory strategy with great promise for the treatment of Cardiovascular diseases (CVDs) (225).…”

“…In the same study, we described a novel pan-STAT1/2/3 inhibitor, C01L_F03, with similar characteristics (225). We proposed that this novel class of inhibitors could be implemented in a multi-STAT inhibitory strategy with great promise for the treatment of Cardiovascular diseases (CVDs) (225). Accordingly, blocking of IRF-DNA binding by IRF-specific or pan-IRF inhibitors presents itself as a promising therapeutic tool to combat a wide range of immunological diseases.…”

Identification of Biomarkers Associated With CD8+ T Cells in Coronary Artery Disease and Their Pan-Cancer Analysis

“…However, recent studies have found that it is also involved in maintaining starter cells in leukemia and colon cancer metastasis ( 64 , 65 ). It was found that blocking STAT3 activity may be an effective strategy for treating CAD ( 66 ). STAT3 is often over-activated in various cancers and is associated with tumor immunosuppression and poor prognosis ( 67 ).…”

Transcriptome-wide analysis reveals the coregulation of RNA-binding proteins and alternative splicing genes in the development of atherosclerosis

“…The signal transducer and activator of transcription (STAT) family includes STAT1, STAT2, and STAT3, which transmit signals from the proinflammatory cytokines interferon (IFN)α and IFNγ and pattern recognition receptor (PRR) Toll-like receptors, which are found in blood vessels. An inflammatory environment is formed under the vessel membrane to promote atherosclerosis 61 , 62 . The transcription factor ERG is essential for endothelial homeostasis, driving the expression of lineage genes and suppressing proinflammatory genes, all of which are associated with atherosclerosis 63 , 64 .…”