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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening
Ka-Ho Leung1, Li-Juan Liu2, Sheng Lin1
1Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
Abstract:
STAT3 modulates the transcription of a wide variety of regulatory genes involved in cell proliferation, differentiation, migration, apoptosis, and other critical cellular functions. Constitutive activation of STAT3 has been detected in a wide spectrum of human malignancies. A pharmacophore model constructed from a training set of STAT3 inhibitors binding to the SH2 domain was used to screen an in-house database of compounds, from which azepine 1 emerged as a top candidate. Compound 1 inhibited STAT3 DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with comparable potency to the well-known STAT3 inhibitor S3I-201. A fluorescence polarization assay revealed that compound 1 targeted the SH2 domain of STAT3. Furthermore, compound 1 inhibited STAT3 phosphorylation in cells without affecting the total expression of STAT3. This study also validates the use of pharmacophore modeling to identify inhibitors of protein-protein interactions.
Insights
Researchers identified a novel azepine compound that inhibits Signal Transducer and Activator of Transcription 3 (STAT3) DNA-binding activity and phosphorylation. This STAT3 inhibitor shows promise for cancer therapy by targeting protein-protein interactions.
Area of Science:
- Molecular Biology
- Medicinal Chemistry
- Drug Discovery
Background:
- Signal Transducer and Activator of Transcription 3 (STAT3) is crucial for cell functions and often constitutively activated in human cancers.
- STAT3's role in cell proliferation, differentiation, migration, and apoptosis makes it a significant target for cancer therapeutics.
Purpose of the Study:
- To identify novel STAT3 inhibitors using pharmacophore modeling.
- To characterize the mechanism of action of a newly identified STAT3 inhibitor, azepine 1.
Main Methods:
- Pharmacophore modeling was employed to screen an in-house compound database.
- In vitro assays assessed STAT3 DNA-binding activity.
- Cellular assays evaluated STAT3-directed transcription and phosphorylation.
- Fluorescence polarization assays confirmed target engagement.
Main Results:
- Azepine 1 was identified as a potent STAT3 inhibitor.
- Compound 1 demonstrated efficacy in inhibiting STAT3 DNA-binding and transcription in vitro and in cellulo.
- Fluorescence polarization confirmed azepine 1 targets the SH2 domain of STAT3.
- Azepine 1 inhibited STAT3 phosphorylation without altering total STAT3 expression.
Conclusions:
- Pharmacophore modeling is a validated approach for discovering protein-protein interaction inhibitors.
- Azepine 1 represents a promising lead compound for developing novel STAT3-targeted cancer therapies.
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