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 1074-5521Full text not available from this repository.
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.
|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|
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