Assays for HSP90 and inhibitors

Aherne, Wynne, Maloney, Alison, Prodromou, Chrisostomos, Rowlands, Martin G, Hardcastle, Anthea, Boxall, Katherine, Clarke, Paul, Walton, Michael I, Pearl, Laurence and Workman, Paul (2003) Assays for HSP90 and inhibitors. Methods in Molecular Medicine, 85. pp. 149-161. ISSN 1543-1894

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The 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).

Item Type: Article
Keywords: Adenosine Triphosphatases/analysis Antineoplastic Agents/*pharmacology Biological Markers Blotting, Western Colorimetry Drug Design Enzyme-Linked Immunosorbent Assay HSP90 Heat-Shock Proteins/*analysis/*antagonists & inhibitors Humans L-Lactate Dehydrogenase/metabolism Neoplasm Proteins/*analysis/antagonists & inhibitors Protein Folding Pyruvate Kinase/metabolism Rosaniline Dyes
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Chrisostomos Prodromou
Date Deposited: 25 Feb 2015 06:50
Last Modified: 25 Feb 2015 06:50
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