Abstract
Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been linked to several processes that are critical for oncogenic transformation, cancer progression, cancer cell proliferation, survival, drug resistance and metastasis. Inhibition of STAT3 signaling has shown a striking ability to inhibit cancer cell growth and therefore, STAT3 has become a promising target for anti-cancer drug development. The aim of this study was to identify novel inhibitors of STAT-dependent gene transcription. A cellular reporter-based system for monitoring STAT3 transcriptional activity was developed which was suitable for high-throughput screening (Z’ = 0,8). This system was used to screen a library of 28,000 compounds (the ENAMINE Drug-Like Diversity Set). Following counter-screenings and toxicity studies, we identified four hit compounds that were subjected to detailed biological characterization. Of the four hits, KI16 stood out as the most promising compound, inhibiting STAT3 phosphorylation and transcriptional activity in response to IL6 stimulation. In silico docking studies showed that KI16 had favorable interactions with the STAT3 SH2 domain, however, no inhibitory activity could be observed in the STAT3 fluorescence polarization assay. KI16 inhibited cell viability preferentially in STAT3-dependent cell lines. Taken together, using a targeted, cell-based approach, novel inhibitors of STAT-driven transcriptional activity were discovered which are interesting leads to pursue further for the development of anti-cancer therapeutic agents.
Highlights
In order to define compounds with Signal Transducer and Activator of Transcription 3 (STAT3) inhibitory activity, we used the stimulation with interleukin 6 (IL6), a multifunctional cytokine involved in STAT signaling in processes of inflammation and oncogenesis [31]
When IL6 binds to its receptor, the associated Janus Kinases (JAKs) are activated, inducing STAT phosphorylation and subsequent transcription factor activity
In order to understand the mechanism of action of the selected compounds, we investigated their effect on the phosphorylation status of STAT3 (Fig 4A), STAT1 (Fig 4B) and the upstream kinases JAK1 and JAK2 upon 30 min of IL6 stimulation (Fig 4C)
Summary
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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