Following the design path of isoform-selective Hsp90 inhibitors : small differences, great opportunities

Dernovšek, Jaka (author), Tomašič, Tihomir (author)

The heat shock protein 90 (Hsp90) family consists of four highly conserved isoforms: the mitochondrial TRAP-1, the endoplasmic reticulum-localised Grp94, and the cytoplasmic Hsp90α and Hsp90β. Since the late 1990s, this family has been extensively studied as a potential target for the treatment of cancer, neurological disorders, and infectious diseases. The initial approach was to develop non-selective, so-called pan-Hsp90 ATP-competitive inhibitors of the N-terminal domain. Many of these agents were tested in clinical trials, mainly for the treatment of cancer, but none of them succeeded in the clinic. This was mainly due to the lack of efficacy and various toxicities associated with the induction of heat shock response (HSR). This lack of success has prompted a turn to new approaches of Hsp90 inhibition. Thus, inhibitors selective for a particular isoform of Hsp90 have been developed. These isoform-selective inhibitors do not induce HSR and have a more targeted effect because not all client proteins are equally dependent on all four paralogues of Hsp90. However, it is extremely difficult to develop such selective compounds because the family is highly conserved. Hsp90α and Hsp90β have an amazing 95% identity of the N-terminal ATP binding site, differing only in two amino acid residues. Therefore, the focus of this review is to fully elucidate the key structural features of the selective inhibitor classes in terms of binding site dissimilarities. In addition to a methodological characterisation of the structure-activity relationships, the main advantages of selective inhibition of the TRAP-1, Grp94, Hsp90α and Hsp90β isoforms are discussed.

• Language: English
• Keywords: cancer, drug design, Hsp90, inhibitor, selectivity
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 20 str.
• Numbering: Vol. 245, art. 108396
• PID: 20.500.12556/RUL-148678
• UDC: 615.4:54
• ISSN on article: 0163-7258
• DOI: 10.1016/j.pharmthera.2023.108396
• COBISS.SI-ID: 147241219
• Publication date in RUL: 29.08.2023

Record is a part of a journal

• Title: Pharmacology & therapeutics
• Shortened title: Pharmacol. ther.
• Publisher: Elsevier
• ISSN: 0163-7258
• COBISS.SI-ID: 26118144

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: zasnova zdravila, selektivnost, inhibitorji, Hsp90, rak, medicina, farmacevtska kemija

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0208
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

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