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Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay
Published on: July 21, 2021
Optimization and biological evaluation of celastrol derivatives as Hsp90-Cdc37 interaction disruptors with improved
Fen Jiang1, Hui-Jie Wang1, Qi-Chao Bao1
1State 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.
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.
Insights
Researchers developed new celastrol derivatives to disrupt the Heat Shock Protein 90 (Hsp90)-Cdc37 interaction, a key pathway in cancer. The derivative CEL20 shows promise as an effective cancer therapeutic by inhibiting tumor growth and promoting cell death.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Heat Shock Protein 90 (Hsp90) is a crucial molecular target in cancer therapy due to its role in cancer cell growth and survival.
- The cochaperone Cdc37 facilitates Hsp90 client association, promoting malignant tumor development.
- Disrupting the Hsp90-Cdc37 interaction offers a novel therapeutic strategy for cancer treatment.
Purpose of the Study:
- To investigate the structure-activity relationship of celastrol derivatives as Hsp90-Cdc37 disruptors.
- To enhance the druglike properties of celastrol derivatives for potential oncology therapeutics.
- To identify novel Hsp90-Cdc37 disruptors for cancer therapy.
Main Methods:
- Design and synthesis of 23 celastrol derivatives.
- Determination of biological activities, including Hsp90-Cdc37 disruption and anti-proliferative effects.
- Evaluation of physicochemical and druglike properties of the synthesized compounds.
Main Results:
- The derivative CEL20 demonstrated enhanced Hsp90-Cdc37 disruption activity.
- CEL20 exhibited significant anti-proliferative effects and improved druglike properties.
- CEL20 induced kinase client degradation, cell cycle arrest, and apoptosis in Panc-1 cancer cells.
Conclusions:
- Celastrol derivatives, particularly CEL20, represent promising candidates for novel Hsp90-Cdc37 disruptors in cancer therapy.
- The study provides a valuable reference for the discovery and development of new oncology therapeutics targeting the Hsp90 pathway.
- Targeting the Hsp90-Cdc37 interaction is a viable strategy for inhibiting cancer progression.
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