The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors

Bioorg Med Chem Lett. 2005 Jul 15;15(14):3338-43. doi: 10.1016/j.bmcl.2005.05.046.

Abstract

High-throughput screening identified the 3,4-diarylpyrazole CCT018159 as a novel and potent (7.1 microM) inhibitor of Hsp90 ATPase activity. Here, we describe the synthesis of CCT018159 and a number of close analogues together with data on their biochemical properties. Some initial structure-activity relationships are discussed, as well as the crystal structure of CCT018159 bound to Hsp90.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Heterocyclic Compounds, 2-Ring* / chemical synthesis
  • Heterocyclic Compounds, 2-Ring* / chemistry
  • Heterocyclic Compounds, 2-Ring* / pharmacology
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Molecular Conformation
  • Protein Conformation
  • Pyrazoles* / chemical synthesis
  • Pyrazoles* / chemistry
  • Pyrazoles* / classification
  • Pyrazoles* / pharmacology
  • Structure-Activity Relationship
  • Yeasts / chemistry
  • Yeasts / enzymology

Substances

  • CCT018159
  • Enzyme Inhibitors
  • HSP90 Heat-Shock Proteins
  • Heterocyclic Compounds, 2-Ring
  • Pyrazoles
  • Adenosine Triphosphatases

Associated data

  • PDB/2BRC
  • PDB/2BRE