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Assays for HSP90 and inhibitors
journal contribution
posted on 2023-06-08, 14:42 authored by Wynne Aherne, Alison Maloney, Chrisostomos ProdromouChrisostomos Prodromou, Martin G Rowlands, Anthea Hardcastle, Katherine Boxall, Paul Clarke, Michael I Walton, Laurence PearlLaurence Pearl, Paul WorkmanThe molecular chaperone HSP90 is currently under investigation as a promising target for anticancer drug discovery. It constitutes 1–2% of total cellular protein and is present in the cell as a dimer in association with a number of other proteins (1). HSP90 is involved in ensuring adequate protein folding and preventing non-specific aggregation of proteins following chemical mutation or stress (2). Under physiological conditions, together with its endoplasmic reticulum homolog GRP94, HSP90 plays a housekeeping role in the cell, maintaining the conformational stability and maturation of several key client proteins, including oncogenic kinases (e.g., ERBB2, RAF-1, CDK4, and LCK), steroid receptors, and mutant TP53 (3). A number of HSP90 inhibitors have already been identified. These include the benzoquinone ansamycin natural product geldanamycin and its analog, 17-allylamino-17-demethoxy-geldanamycin (17AAG), together with the chemically dissimilar natural product radicicol. The predominant mechanism of action of these agents involves binding to HSP90 at the ATP binding site in the N-terminal domain of the protein, leading to inhibition of the intrinsic ATPase activity of HSP90 (4–6). Inhibition of HSP90 ATPase activity prevents recruitment of co-chaperones and encourages the formation of a type of HSP90 heterocomplex from which these client proteins are targeted for degradation via the ubiquitin proteosome pathway (3,7).
History
Publication status
- Published
Journal
Methods in Molecular MedicineISSN
1543-1894Publisher
Springer VerlagExternal DOI
Volume
85Page range
149-161Department affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2015-02-25Usage metrics
Categories
No categories selectedKeywords
Adenosine Triphosphatases/analysisAntineoplastic Agents/*pharmacologyBiological MarkersBlottingWesternColorimetryDrug DesignEnzyme-Linked Immunosorbent AssayHSP90 Heat-Shock Proteins/*analysis/*antagonists & inhibitorsHumansL-Lactate Dehydrogenase/metabolismNeoplasm Proteins/*analysis/antagonists & inhibitorsProtein FoldingPyruvate Kinase/metabolismRosaniline Dyes
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