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; Dik Lung Ma

doi:10.1016/j.ymeth.2014.07.010

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, Dik Lung Ma

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal › Journal article › peer-review

22 Citations (Scopus)

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.

Original language	English
Pages (from-to)	38-43
Number of pages	6
Journal	Methods
Volume	71
Issue number	C
DOIs	https://doi.org/10.1016/j.ymeth.2014.07.010
Publication status	Published - 2015

Scopus Subject Areas

Molecular Biology
General Biochemistry,Genetics and Molecular Biology

User-Defined Keywords

Pharmacophore
Protein-protein interaction
STAT3
Virtual screening

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ymeth.2014.07.010

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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.",

keywords = "Pharmacophore, Protein-protein interaction, STAT3, Virtual screening",

author = "Leung, {Ka Ho} and Liu, {Li Juan} and Sheng Lin and Lihua Lu and Zhong, {Hai Jing} and Dewi Susanti and Weidong Rao and Modi Wang and Che, {Weng Ian} and Chan, {Daniel Shiu Hin} and Leung, {Chung Hang} and Chan, {Philip Wai Hong} and Ma, {Dik Lung}",

note = "Funding Information: This work is supported by Hong Kong Baptist University ( FRG2/12-13/021 and FRG2/13-14/008 ), Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIR-SCM, HKBU), the Health and Medical Research Fund ( HMRF/13121482 ), the Research Grants Council ( HKBU/201811 , HKBU/204612 , and HKBU/201913 ), the French National Research Agency/Research Grants Council Joint Research Scheme ( A-HKBU201/12 ), the Science and Technology Development Fund , Macau SAR ( 103/2012/A3 ), the University of Macau ( MYRG091(Y3-L2)-ICMS12-LCH , MYRG121(Y3-L2)-ICMS12-LCH and MRG023/LCH/2013/ICMS ), University Research Committee Grant ( RG55/06 ) from Nanyang Technological University and Science and Engineering Research Council Grant ( 092 101 0053 ) from A∗STAR , Singapore. ",

year = "2015",

doi = "10.1016/j.ymeth.2014.07.010",

language = "English",

volume = "71",

pages = "38--43",

journal = "Methods",

issn = "1046-2023",

publisher = "Academic Press Inc.",

number = "C",

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T1 - Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening

AU - Leung, Ka Ho

AU - Liu, Li Juan

AU - Lin, Sheng

AU - Lu, Lihua

AU - Zhong, Hai Jing

AU - Susanti, Dewi

AU - Rao, Weidong

AU - Wang, Modi

AU - Che, Weng Ian

AU - Chan, Daniel Shiu Hin

AU - Leung, Chung Hang

AU - Chan, Philip Wai Hong

AU - Ma, Dik Lung

N1 - Funding Information: This work is supported by Hong Kong Baptist University ( FRG2/12-13/021 and FRG2/13-14/008 ), Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIR-SCM, HKBU), the Health and Medical Research Fund ( HMRF/13121482 ), the Research Grants Council ( HKBU/201811 , HKBU/204612 , and HKBU/201913 ), the French National Research Agency/Research Grants Council Joint Research Scheme ( A-HKBU201/12 ), the Science and Technology Development Fund , Macau SAR ( 103/2012/A3 ), the University of Macau ( MYRG091(Y3-L2)-ICMS12-LCH , MYRG121(Y3-L2)-ICMS12-LCH and MRG023/LCH/2013/ICMS ), University Research Committee Grant ( RG55/06 ) from Nanyang Technological University and Science and Engineering Research Council Grant ( 092 101 0053 ) from A∗STAR , Singapore.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Pharmacophore

KW - Protein-protein interaction

KW - STAT3

KW - Virtual screening

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U2 - 10.1016/j.ymeth.2014.07.010

DO - 10.1016/j.ymeth.2014.07.010

M3 - Journal article

C2 - 25160651

AN - SCOPUS:84927728260

SN - 1046-2023

VL - 71

SP - 38

EP - 43

JO - Methods

JF - Methods

IS - C

ER -

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

Abstract

Scopus Subject Areas

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UN SDGs

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