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

Autor: Jianping Liu, Brent D. G. Page, Matheus Dyczynski, Katja Pokrovskaja Tamm, Yasmin Yu, Martin Haraldsson, Thomas Helleday, Dan Grandér, Sander Busker, Caroline Palm Apergi, Iryna Kolosenko
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Cell signaling
Cell
Protein domains
lcsh:Medicine
Apoptosis
Signal transduction
Biochemistry
SH2 domain
0302 clinical medicine
Transcription (biology)
Neoplasms
Tumor Cells
Cultured
Post-Translational Modification
Phosphorylation
STAT3
lcsh:Science
DU145 cells
Multidisciplinary
biology
Chemistry
Luciferase Assay
Small molecule
Enzymes
Cell biology
STAT signaling
Bioassays and Physiological Analysis
medicine.anatomical_structure
Drug development
030220 oncology & carcinogenesis
Cell lines
Oxidoreductases
Biological cultures
Luciferase
Research Article
STAT3 Transcription Factor
Antineoplastic Agents
Library Screening
Small Molecule Libraries
03 medical and health sciences
medicine
Humans
Viability assay
Molecular Biology Techniques
Molecular Biology
Cell Proliferation
Enzyme Assays
Molecular Biology Assays and Analysis Techniques
lcsh:R
Biology and Life Sciences
Proteins
High Throughput Screening
High-Throughput Screening Assays
Research and analysis methods
030104 developmental biology
Cancer cell
Enzymology
biology.protein
STAT protein
lcsh:Q
Biochemical Analysis
Zdroj: PLoS ONE, Vol 12, Iss 6, p e0178844 (2017)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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