In silico discovery and optimisation of a novel structural class of Hsp90 C-terminal domain inhibitors

Zajec, Živa (author), Dernovšek, Jaka (author), Gobec, Martina (author), Tomašič, Tihomir (author)

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 TVS-23 showing antiproliferative activity with an IC50 value of 26.4 ± 1.1 µM. We report here the optimisation, synthesis and biological evaluation of TVS-23 analogues. Several analogues showed significantly enhanced antiproliferative activities in MCF-7 breast cancer and SK-N-MC Ewing sarcoma cell lines, with 7l being the most potent (IC50 = 1.4 ± 0.4 µM MCF-7; IC50 = 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.

• Language: English
• Keywords: allosteric, cancer, heat shock, Hsp90, inhibitor, virtual screening
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication date: 24.06.2022
• Year: 2022
• Number of pages: 23 str.
• Numbering: Vol. 12, iss. 7, art 884
• PID: 20.500.12556/RUL-137880-7c8e690d-baec-291e-1804-da01785a1b6b
• UDC: 615.4:54:616-006
• ISSN on article: 2218-273X
• DOI: 10.3390/biom12070884
• COBISS.SI-ID: 113870339
• Publication date in RUL: 05.07.2022

Record is a part of a journal

• Title: Biomolecules
• Shortened title: Biomolecules
• Publisher: MDPI
• ISSN: 2218-273X
• COBISS.SI-ID: 519952921

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 05.07.2022

Secondary language

• Language: Slovenian
• Keywords: alosterični, toplotni šok, Hsp90, inhibitorji, virtualno rešetanje

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: N1-0208
• Name: Avtomorfizmi in izomorfizmi končnih grafov

• Funder: ARRS - Slovenian Research Agency
• Project number: J1-1717
• Name: Razvoj novih zaviralcev Hsp90 s protitumornim delovanjem