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 con...
| Main Authors: | , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2016
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/82160 http://hdl.handle.net/10220/41144 |
| _version_ | 1824456565760983040 |
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| author | Leung, Ka-Ho Liu, Li-Juan Lin, Sheng Lu, Lihua Zhong, Hai-Jing Susanti, Dewi Rao, Weidong Wang, Modi Che, Weng Ian Chan, Daniel Shiu-Hin Leung, Chung-Hang Chan, Philip Wai Hong Ma, Dik-Lung |
| author2 | School of Physical and Mathematical Sciences |
| author_facet | School of Physical and Mathematical Sciences Leung, Ka-Ho Liu, Li-Juan Lin, Sheng Lu, Lihua Zhong, Hai-Jing Susanti, Dewi Rao, Weidong Wang, Modi Che, Weng Ian Chan, Daniel Shiu-Hin Leung, Chung-Hang Chan, Philip Wai Hong Ma, Dik-Lung |
| author_sort | Leung, Ka-Ho |
| collection | NTU |
| description | 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. |
| first_indexed | 2025-02-19T03:56:08Z |
| format | Journal Article |
| id | ntu-10356/82160 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:56:08Z |
| publishDate | 2016 |
| record_format | dspace |
| spelling | ntu-10356/821602020-03-07T12:31:32Z Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening Leung, Ka-Ho Liu, Li-Juan Lin, Sheng Lu, Lihua Zhong, Hai-Jing Susanti, Dewi Rao, Weidong Wang, Modi Che, Weng Ian Chan, Daniel Shiu-Hin Leung, Chung-Hang Chan, Philip Wai Hong Ma, Dik-Lung School of Physical and Mathematical Sciences Pharmacophore STAT3 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. ASTAR (Agency for Sci., Tech. and Research, S’pore) 2016-08-16T08:22:32Z 2019-12-06T14:47:45Z 2016-08-16T08:22:32Z 2019-12-06T14:47:45Z 2014 Journal Article Leung, K.-H., Liu, L.-J., Lin, S., Lu, L., Zhong, H.-J., Susanti, D., et al. (2014). Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening. Methods, 71, 38-43. 1046-2023 https://hdl.handle.net/10356/82160 http://hdl.handle.net/10220/41144 10.1016/j.ymeth.2014.07.010 en Methods © 2014 Elsevier Inc. |
| spellingShingle | Pharmacophore STAT3 Leung, Ka-Ho Liu, Li-Juan Lin, Sheng Lu, Lihua Zhong, Hai-Jing Susanti, Dewi Rao, Weidong Wang, Modi Che, Weng Ian Chan, Daniel Shiu-Hin Leung, Chung-Hang Chan, Philip Wai Hong Ma, Dik-Lung Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening |
| title | Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening |
| title_full | Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening |
| title_fullStr | Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening |
| title_full_unstemmed | Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening |
| title_short | Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening |
| title_sort | discovery of a small molecule inhibitor of stat3 by ligand based pharmacophore screening |
| topic | Pharmacophore STAT3 |
| url | https://hdl.handle.net/10356/82160 http://hdl.handle.net/10220/41144 |
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