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Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms

Wright, L., Barril, X., Dymock, B., Sheridan, L., Surgenor, A., Beswick, M., Drysdale, M., Collier, A., Massey, A., Davies, N., Fink, A., Fromont, C., Aherne, W., Boxall, K., Sharp, S., Workman, P. and Hubbard, R.E. (2004) Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms. Chemistry & Biology, 13 (6). pp. 775-785. ISSN 1074-5521

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Abstract

Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90α N-terminal domain complexed with the purine-based inhibitor, PU3, and analogs with enhanced potency both in enzyme and cell-based assays. The compounds induce upregulation of HSP70 and downregulation of the known HSP90 client proteins Raf-1, CDK4, and ErbB2, confirming that the molecules inhibit cell growth by a mechanism dependent on HSP90 inhibition. We have also determined the first structure of the N-terminal domain of HSP90β, complexed with PU3. The structures allow a detailed rationale to be developed for the observed affinity of the PU3 class of compounds for HSP90 and also provide a structural framework for design of compounds with improved binding affinity and drug-like properties.

Item Type: Article
Institution: The University of York
Academic Units: The University of York > Chemistry (York)
Depositing User: York RAE Import
Date Deposited: 03 Sep 2009 14:56
Last Modified: 03 Sep 2009 14:56
Published Version: http://dx.doi.org/10.1016/j.chembiol.2004.03.033
Status: Published
Publisher: Elsevier
Identification Number: 10.1016/j.chembiol.2004.03.033
URI: http://eprints.whiterose.ac.uk/id/eprint/5882

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