Department of Chemistry
Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening
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.
Pharmacophore, STAT3, Virtual screening, Protein–protein interaction
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Leung, K., Liu, L., Lin, S., Lu, L., Zhong, H., Susanti, D., Rao, W., Wang, M., Che, W., Chan, D., Leung, C., Chan, P., & Ma, D. (2015). Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening. Methods, 71, 38-43. https://doi.org/10.1016/j.ymeth.2014.07.010