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

Chem Biol. 2004 Jun;11(6):775-85. doi: 10.1016/j.chembiol.2004.03.033.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemistry*
  • Adenine / metabolism
  • Adenine / pharmacology
  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Anisoles / chemistry*
  • Anisoles / metabolism
  • Anisoles / pharmacology
  • Binding Sites
  • Cell Division / drug effects
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / chemistry*
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Protein Isoforms
  • Protein Structure, Tertiary
  • Purines / chemistry*
  • Purines / metabolism
  • Purines / pharmacology
  • Structure-Activity Relationship

Substances

  • 9-(n-butyl)-8-((3,4,5-trimethoxyphenyl)methyl)adenine
  • Anisoles
  • Enzyme Inhibitors
  • HSP90 Heat-Shock Proteins
  • HSP90AB1 protein, human
  • Ligands
  • Protein Isoforms
  • Purines
  • Adenosine Triphosphatases
  • Adenine

Associated data

  • PDB/1UY6
  • PDB/1UY7
  • PDB/1UY8
  • PDB/1UY9
  • PDB/1UYC
  • PDB/1UYD
  • PDB/1UYE
  • PDB/1UYF
  • PDB/1UYG
  • PDB/1UYH
  • PDB/1UYI
  • PDB/1UYK
  • PDB/1UYL
  • PDB/1UYM