| Autor: |
Howes R; Vernalis (Cambridge), Granta Park, Great Abington, Cambridge CB1 6GB, UK. r.howes@vernalis.com, Barril X, Dymock BW, Grant K, Northfield CJ, Robertson AG, Surgenor A, Wayne J, Wright L, James K, Matthews T, Cheung KM, McDonald E, Workman P, Drysdale MJ |
| Jazyk: |
angličtina |
| Zdroj: |
Analytical biochemistry [Anal Biochem] 2006 Mar 15; Vol. 350 (2), pp. 202-13. Date of Electronic Publication: 2006 Jan 23. |
| DOI: |
10.1016/j.ab.2005.12.023 |
| Abstrakt: |
Hsp90 encodes a ubiquitous molecular chaperone protein conserved among species which acts on multiple substrates, many of which are important cell-signaling proteins. Inhibition of Hsp90 function has been promoted as a mechanism to degrade client proteins involved in tumorigenesis and disease progression. Several assays to monitor inhibition of Hsp90 function currently exist but are limited in their use for a drug discovery campaign. Using data from the crystal structure of an initial hit compound, we have developed a fluorescence polarization assay to monitor binding of compounds to the ATP-binding site of Hsp90. This assay is very robust (Z' > 0.9) and can detect affinity of compounds with IC50s to 40 nM. We have used this assay in conjunction with cocrystal structures of small molecules to drive a structure-based design program aimed at the discovery and optimization of a novel class of potent Hsp90 inhibitors. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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