Novel, Potent Small-Molecule Inhibitors of the Molecular Chaperone Hsp90 Discovered Through Structure-Based Design

J Med Chem. 2005 Jun 30;48(13):4212-5. doi: 10.1021/jm050355z.

Abstract

The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology
  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology
  • Binding Sites
  • Drug Design
  • Glycine
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / chemistry
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation
  • Structure-Activity Relationship

Substances

  • Amides
  • Amines
  • HSP90 Heat-Shock Proteins
  • Adenosine Triphosphate
  • Glycine