Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors
AbstractTargeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and t...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2290912 |
| _version_ | 1797394378813079552 |
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| author | Yajun Liu Chenyao Li Yajing Li Shuming Zhang Ning Zhang Xiaobo Bian Shutao Tan |
| author_facet | Yajun Liu Chenyao Li Yajing Li Shuming Zhang Ning Zhang Xiaobo Bian Shutao Tan |
| author_sort | Yajun Liu |
| collection | DOAJ |
| description | AbstractTargeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and the present inhibitors. We collected seven classical and structurally diverse HSP90 C-terminal inhibitors and constructed a ligand-based pharmacophore model. The subsequent virtual screening and structural optimisation led to the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors. 9 and 27 exhibited strong antitumour activity in vitro by inhibiting proliferation and inducing apoptosis in multiple cancer cell lines. These compounds disrupted the interaction between HSP90 C-terminus and peptidylprolyl isomerase D, exerting a stronger inhibitory effect than novobiocin. 27 significantly induced the degradation of HSP90 clients without triggering heat shock response. In an in vivo study using 4T1 mice breast cancer models, 9 showed a potent antitumour effect without obvious toxicity. |
| first_indexed | 2024-03-09T00:18:53Z |
| format | Article |
| id | doaj.art-f0a0d0ea2114422599d699e4260de5d4 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-03-09T00:18:53Z |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-f0a0d0ea2114422599d699e4260de5d42023-12-12T07:23:44ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2023.2290912Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitorsYajun Liu0Chenyao Li1Yajing Li2Shuming Zhang3Ning Zhang4Xiaobo Bian5Shutao Tan6School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaDepartment of Oncology, Shengjing Hospital of China Medical University, Shenyang, ChinaDepartment of Urology, Shengjing Hospital of China Medical University, Shenyang, ChinaAbstractTargeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and the present inhibitors. We collected seven classical and structurally diverse HSP90 C-terminal inhibitors and constructed a ligand-based pharmacophore model. The subsequent virtual screening and structural optimisation led to the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors. 9 and 27 exhibited strong antitumour activity in vitro by inhibiting proliferation and inducing apoptosis in multiple cancer cell lines. These compounds disrupted the interaction between HSP90 C-terminus and peptidylprolyl isomerase D, exerting a stronger inhibitory effect than novobiocin. 27 significantly induced the degradation of HSP90 clients without triggering heat shock response. In an in vivo study using 4T1 mice breast cancer models, 9 showed a potent antitumour effect without obvious toxicity.https://www.tandfonline.com/doi/10.1080/14756366.2023.2290912HSP90 C-terminuspharmacophore modellingvirtual screeningantitumourapoptosis |
| spellingShingle | Yajun Liu Chenyao Li Yajing Li Shuming Zhang Ning Zhang Xiaobo Bian Shutao Tan Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry HSP90 C-terminus pharmacophore modelling virtual screening antitumour apoptosis |
| title | Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors |
| title_full | Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors |
| title_fullStr | Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors |
| title_full_unstemmed | Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors |
| title_short | Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors |
| title_sort | ligand based pharmacophore modelling structure optimisation and biological evaluation for the identification of 2 heteroarylthio n arylacetamides as novel hsp90 c terminal inhibitors |
| topic | HSP90 C-terminus pharmacophore modelling virtual screening antitumour apoptosis |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2290912 |
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