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

Fen Jiang, Hui Jie Wang, Qi Chao Bao, Lei Wang, Yu Hui Jin, Qiong Zhang, Di Jiang, Qi Dong You, Xiao Li Xu

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5431-5439
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number21
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • Celastrol
  • Druglike properties
  • HTRF
  • Hsp90–Cdc37 interaction
  • Structure–activity relationship

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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