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Chem Biol. 2004 Jun;11(6):775-85.

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

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  • 1Vernalis (R&D) Ltd., Granta Park, Abington, Cambridge CB1 6GB, UK.

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 HSP90alpha 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 HSP90beta, 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.

PMID:
15217611
[PubMed - indexed for MEDLINE]
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