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

L Wright, X Barril, B Dymock, L Sheridan, A Surgenor, M Beswick, M Drysdale, A Collier, A Massey, N Davies, A Fink, C Fromont, W Aherne, K Boxall, S Sharp, P Workman, R E Hubbard

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)775-785
Number of pages11
JournalChemistry & Biology
Volume11
Issue number6
DOIs
Publication statusPublished - Jun 2004

Keywords

  • IN-VIVO FUNCTION
  • MOLECULAR CHAPERONE
  • ATP-BINDING
  • PROTEIN MODELS
  • CANCER CELLS
  • HEAT-SHOCK-PROTEIN-90
  • REFINEMENT
  • HYDROLYSIS
  • RADICICOL
  • TARGET

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