title: Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening.
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.
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Ka-Ho
authors.initials: KH
authors.lastname: Leung
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Zhong
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.
authors.forename: Dewi
authors.initials: D
authors.lastname: Susanti
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.
authors.forename: Weidong
authors.initials: W
authors.lastname: Rao
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Modi
authors.initials: M
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Weng Ian
authors.initials: WI
authors.lastname: Che
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Daniel Shiu-Hin
authors.initials: DS
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: duncanleung@umac.mo.
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore. Electronic address: waihong@ntu.edu.sg.
authors.forename: Philip Wai Hong
authors.initials: PW
authors.lastname: Chan
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. Electronic address: edmondma@hkbu.edu.hk.
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
mesh_terms: D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D050796:STAT3 Transcription Factor
keywords: Pharmacophore; Protein–protein interaction; STAT3; Virtual screening