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
Full text not available from this repository.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 |
|---|---|
| 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 |
Actions (login required)
 |
View Item |
