In Silico Discovery and Optimisation of a Novel Structural Class of Hsp90 C-Terminal Domain Inhibitors
Hsp90 is a promising target for the development of novel agents for cancer treatment. The N-terminal Hsp90 inhibitors have several therapeutic limitations, the most important of which is the induction of heat shock response, which can be circumvented by targeting the allosteric binding site on the C...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/7/884 |
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| author | Živa Zajec Jaka Dernovšek Martina Gobec Tihomir Tomašič |
| author_facet | Živa Zajec Jaka Dernovšek Martina Gobec Tihomir Tomašič |
| author_sort | Živa Zajec |
| collection | DOAJ |
| description | Hsp90 is a promising target for the development of novel agents for cancer treatment. The N-terminal Hsp90 inhibitors have several therapeutic limitations, the most important of which is the induction of heat shock response, which can be circumvented by targeting the allosteric binding site on the C-terminal domain (CTD) of Hsp90. In the absence of an Hsp90—CTD inhibitor co-crystal structure, the use of structure-based design approaches for the Hsp90 CTD is difficult and the structural diversity of Hsp90 CTD inhibitors is limited. In this study, we describe the discovery of a novel structural class of Hsp90 CTD inhibitors. A structure-based virtual screening was performed by docking a library of diverse compounds to the Hsp90β CTD binding site. Three selected virtual hits were tested in the MCF-7 breast cancer cell line, with compound <b>TVS-23</b> showing antiproliferative activity with an IC<sub>50</sub> value of 26.4 ± 1.1 µM. We report here the optimisation, synthesis and biological evaluation of <b>TVS-23</b> analogues. Several analogues showed significantly enhanced antiproliferative activities in MCF-7 breast cancer and SK-N-MC Ewing sarcoma cell lines, with <b>7l</b> being the most potent (IC<sub>50 </sub>= 1.4 ± 0.4 µM MCF-7; IC<sub>50</sub> = 2.8 ± 0.4 µM SK-N-MC). The results of this study highlight the use of virtual screening to expand the structural diversity of Hsp90 CTD inhibitors and provide new starting points for further development. |
| first_indexed | 2024-03-09T03:39:41Z |
| format | Article |
| id | doaj.art-a9876a3ccd284e509d41761996b2ff0d |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T03:39:41Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-a9876a3ccd284e509d41761996b2ff0d2023-12-03T14:43:09ZengMDPI AGBiomolecules2218-273X2022-06-0112788410.3390/biom12070884In Silico Discovery and Optimisation of a Novel Structural Class of Hsp90 C-Terminal Domain InhibitorsŽiva Zajec0Jaka Dernovšek1Martina Gobec2Tihomir Tomašič3Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000 Ljubljana, SloveniaHsp90 is a promising target for the development of novel agents for cancer treatment. The N-terminal Hsp90 inhibitors have several therapeutic limitations, the most important of which is the induction of heat shock response, which can be circumvented by targeting the allosteric binding site on the C-terminal domain (CTD) of Hsp90. In the absence of an Hsp90—CTD inhibitor co-crystal structure, the use of structure-based design approaches for the Hsp90 CTD is difficult and the structural diversity of Hsp90 CTD inhibitors is limited. In this study, we describe the discovery of a novel structural class of Hsp90 CTD inhibitors. A structure-based virtual screening was performed by docking a library of diverse compounds to the Hsp90β CTD binding site. Three selected virtual hits were tested in the MCF-7 breast cancer cell line, with compound <b>TVS-23</b> showing antiproliferative activity with an IC<sub>50</sub> value of 26.4 ± 1.1 µM. We report here the optimisation, synthesis and biological evaluation of <b>TVS-23</b> analogues. Several analogues showed significantly enhanced antiproliferative activities in MCF-7 breast cancer and SK-N-MC Ewing sarcoma cell lines, with <b>7l</b> being the most potent (IC<sub>50 </sub>= 1.4 ± 0.4 µM MCF-7; IC<sub>50</sub> = 2.8 ± 0.4 µM SK-N-MC). The results of this study highlight the use of virtual screening to expand the structural diversity of Hsp90 CTD inhibitors and provide new starting points for further development.https://www.mdpi.com/2218-273X/12/7/884allostericcancerheat shockHsp90inhibitorvirtual screening |
| spellingShingle | Živa Zajec Jaka Dernovšek Martina Gobec Tihomir Tomašič In Silico Discovery and Optimisation of a Novel Structural Class of Hsp90 C-Terminal Domain Inhibitors Biomolecules allosteric cancer heat shock Hsp90 inhibitor virtual screening |
| title | In Silico Discovery and Optimisation of a Novel Structural Class of Hsp90 C-Terminal Domain Inhibitors |
| title_full | In Silico Discovery and Optimisation of a Novel Structural Class of Hsp90 C-Terminal Domain Inhibitors |
| title_fullStr | In Silico Discovery and Optimisation of a Novel Structural Class of Hsp90 C-Terminal Domain Inhibitors |
| title_full_unstemmed | In Silico Discovery and Optimisation of a Novel Structural Class of Hsp90 C-Terminal Domain Inhibitors |
| title_short | In Silico Discovery and Optimisation of a Novel Structural Class of Hsp90 C-Terminal Domain Inhibitors |
| title_sort | in silico discovery and optimisation of a novel structural class of hsp90 c terminal domain inhibitors |
| topic | allosteric cancer heat shock Hsp90 inhibitor virtual screening |
| url | https://www.mdpi.com/2218-273X/12/7/884 |
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