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Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening
Leung K.-H.1; Liu L.-J.3; Lin S.1; Lu L.1; Zhong H.-J.3; Susanti D.2; Rao W.2; Wang M.1; Che W.I.3; Chan D.S.H.1; Leung C.-H.3; Chan P.W.H.2; Ma D.-L.1
2015
Source PublicationMethods
ISSN10959130 10462023
Volume71Issue:CPages:38-43
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.

KeywordPharmacophore Protein-protein Interaction Stat3 Virtual Screening
DOI10.1016/j.ymeth.2014.07.010
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemical Research Methods ; Biochemistry & Molecular Biology
WOS IDWOS:000348264200006
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Cited Times [WOS]:19   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorLeung C.-H.; Chan P.W.H.; Ma D.-L.
Affiliation1.Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
2.Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
3.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Leung K.-H.,Liu L.-J.,Lin S.,et al. Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening[J]. Methods,2015,71(C):38-43.
APA Leung K.-H.,Liu L.-J.,Lin S.,Lu L.,Zhong H.-J.,Susanti D.,Rao W.,Wang M.,Che W.I.,Chan D.S.H.,Leung C.-H.,Chan P.W.H.,&Ma D.-L..(2015).Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening.Methods,71(C),38-43.
MLA Leung K.-H.,et al."Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening".Methods 71.C(2015):38-43.
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