Identification of novel small molecules that inhibit STAT3-dependent transcription and function

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 ab...

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Published in:PloS one Vol. 12; no. 6; p. e0178844
Main Authors: Kolosenko, Iryna, Yu, Yasmin, Busker, Sander, Dyczynski, Matheus, Liu, Jianping, Haraldsson, Martin, Palm Apergi, Caroline, Helleday, Thomas, Tamm, Katja Pokrovskaja, Page, Brent D. G., Grander, Dan
Format: Journal Article
Language:English
Published: United States Public Library of Science 21.06.2017
Public Library of Science (PLoS)
Subjects:
Anticancer properties
Antimitotic agents
Antineoplastic agents
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Biochemistry
Biology
Biology and Life Sciences
Biophysics
Biotechnology
Cancer
Cell proliferation
Cell Proliferation - drug effects
Cell survival
Chemical compounds
Cytokines
Docking
Drug development
Drug resistance
Fluorescence
Fluorescence polarization
Gene expression
Genetic aspects
Genetic transformation
Growth factors
High-throughput screening
High-Throughput Screening Assays - methods
Humans
Inhibitors
Interleukin 6
Kinases
Laboratories
Libraries
Medical screening
Metastases
Neoplasms - drug therapy
Neoplasms - pathology
Oncology
Pathology
Pharmacology
Phosphorylation
Physiological aspects
Polarization
Proteins
Research and analysis methods
Risk factors
Signal Transduction
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Stat3 protein
STAT3 Transcription Factor - antagonists & inhibitors
Stimulation
Studies
Toxicity
Transcription activation
Transcription factors
Transformation
Tumor Cells, Cultured
Sweden
ISSN:1932-6203, 1932-6203
Online Access:Get full text
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Summary: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.
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Competing Interests: The authors have declared that no competing interests exist.
Conceptualization: IK DG BDGP.Data curation: IK BDGP.Formal analysis: IK YY BDGP MH.Funding acquisition: DG IK BPGP CPA.Investigation: IK YY BDGP MD JL CPA SB.Methodology: IK JL BPGP YY.Project administration: IK KPT.Resources: DG JL TH CPA.Software: BDGP TH.Supervision: DG BDGP IK KPT.Validation: IK YY JL BDGP.Visualization: IK YY BDGP.Writing – original draft: IK BDGP.Writing – review & editing: IK BDGP KPT DG YY CPA SB MD JL.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0178844