Optimization and biological evaluation of celastrol derivatives as Hsp90-Cdc37 interaction disruptors with improved druglike properties

Bioorg Med Chem. 2016 Nov 1;24(21):5431-5439. doi: 10.1016/j.bmc.2016.08.070. Epub 2016 Sep 1.


Heat shock protein 90 (Hsp90) as a molecular target for oncology therapeutics has attracted much attention in the last decade. The Hsp90 multichaperone complex has important roles in the growth and/or survival of cancer cells. Cdc37, as a cochaperone, associates kinase clients to Hsp90 and promotes the development of malignant tumors. Disrupting the Hsp90-Cdc37 interaction provides an alternative strategy to inhibit the function of Hsp90 for cancer therapy. Celastrol, as a natural product, can disrupt the Hsp90-Cdc37 interaction and induce degradation of kinase clients. The study conducted here attempted to elucidate the structure-activity relationship of celastrol derivatives as Hsp90-Cdc37 disruptors and to improve the druglike properties. 23 celastrol derivatives were designed, synthesized, and the biological activities and physicochemical properties were determined. The derivative CEL20 showed improved Hsp90-Cdc37 disruption activity, anti-proliferative activities as well as druglike properties. Additionally, CEL20 induced clients degradation, cell cycle arrest and apoptosis in Panc-1 cells. This study can provide reference for the discovery of novel Hsp90-Cdc37 disruptors.

Keywords: Celastrol; Druglike properties; HTRF; Hsp90–Cdc37 interaction; Structure–activity relationship.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / chemistry
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chaperonins / antagonists & inhibitors*
  • Chaperonins / chemistry
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / chemistry
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Triterpenes / chemical synthesis
  • Triterpenes / chemistry
  • Triterpenes / pharmacology*


  • Antineoplastic Agents
  • CDC37 protein, human
  • Cell Cycle Proteins
  • HSP90 Heat-Shock Proteins
  • Triterpenes
  • Chaperonins
  • celastrol