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Title: Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening
Authors: Leung, Ka-Ho
Liu, Li-Juan
Lin, Sheng
Lu, Lihua
Zhong, Hai-Jing
Susanti, Dewi
Rao, Weidong
Wang, Modi
Che, Weng Ian
Chan, Daniel Shiu-Hin
Leung, Chung-Hang
Chan, Philip Wai Hong
Ma, Dik-Lung
Keywords: Pharmacophore
Issue Date: 2014
Source: Leung, K.-H., Liu, L.-J., Lin, S., Lu, L., Zhong, H.-J., Susanti, D., et al. (2014). Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening. Methods, 71, 38-43.
Series/Report no.: Methods
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.
ISSN: 1046-2023
DOI: 10.1016/j.ymeth.2014.07.010
Schools: School of Physical and Mathematical Sciences 
Rights: © 2014 Elsevier Inc.
Fulltext Permission: none
Fulltext Availability: No Fulltext
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