Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening

Ka Ho Leung, Li Juan Liu, Sheng Lin, Lihua Lu, Hai Jing Zhong, Dewi Susanti, Weidong Rao, Modi Wang, Weng Ian Che, Daniel Shiu Hin Chan, Chung Hang Leung*, Philip Wai Hong Chan, Edmond Dik Lung MA

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

21 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)38-43
Number of pages6
Issue numberC
Publication statusPublished - 2015

Scopus Subject Areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)

User-Defined Keywords

  • Pharmacophore
  • Protein-protein interaction
  • STAT3
  • Virtual screening


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