2. Academic Validation
  3. Optimization and biological evaluation of celastrol derivatives as Hsp90-Cdc37 interaction disruptors with improved druglike properties

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.
Fen Jiang 1,  Hui-Jie Wang 1,  Qi-Chao Bao 1,  Lei Wang 1,  Yu-Hui Jin 1,  Qiong Zhang 1,  Di Jiang 1,  Qi-Dong You 2,  Xiao-Li Xu 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqidong@gmail.com.
  • 3 State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xuxiao_li@126.com.
PMID: 27647369 DOI: 10.1016/j.bmc.2016.08.070
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.

Keywords

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

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