Related Experiment Video
Updated: Jul 8, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Enniatin A Analogues as Novel Hsp90 Inhibitors that Modulate Triple-Negative Breast Cancer
Michael A Serwetnyk1, Vincent M Crowley2, Christopher M Brackett1
1Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, The University of Notre Dame, Notre Dame, Indiana 46556, United States.
Abstract:
The 90 kilo-Dalton heat shock protein (Hsp90) is a molecular chaperone that facilitates the maturation of nascent polypeptides into their biologically active conformation. Because many of the >400 known client protein substrates are implicated in the development/progression of cancer, it is hypothesized that Hsp90 inhibition will simultaneously shut down numerous oncogenic pathways. Unfortunately, most of the small molecule Hsp90 inhibitors that have undergone clinical evaluation thus far have failed due to various toxicities. Therefore, the disruption of Hsp90 protein-protein interactions with cochaperones and/or client substrates has been proposed as an alternative way to achieve Hsp90 inhibition without such adverse events. The hexadepsipeptide Enniatin A (EnnA) has recently been reported to be one such inhibitor that also manifests immunogenic activity. Herein, we report preliminary structure-activity relationship (SAR) studies to determine the structural features that confer this unprecedented activity for an Hsp90 inhibitor. Our studies find that EnnA's branching moieties are necessary for its activity, but some structural modifications are tolerated.
Insights
The hexadepsipeptide Enniatin A (EnnA) shows promise as an Hsp90 inhibitor with immunogenic activity. Structure-activity studies reveal that EnnA’s branching groups are crucial for its effectiveness, though some modifications are acceptable.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Heat shock protein 90 (Hsp90) is a molecular chaperone crucial for cancer-related protein maturation.
- Hsp90 client proteins are implicated in numerous oncogenic pathways.
- Current small molecule Hsp90 inhibitors face toxicity issues in clinical trials.
Purpose of the Study:
- To explore Hsp90 inhibition via disruption of protein-protein interactions.
- To investigate the structure-activity relationships (SAR) of Enniatin A (EnnA) as an Hsp90 inhibitor.
- To identify structural features responsible for EnnA's dual Hsp90 inhibitory and immunogenic activity.
Main Methods:
- Preliminary structure-activity relationship (SAR) studies were conducted.
- The impact of structural modifications on EnnA's activity was assessed.
Main Results:
- Enniatin A (EnnA) exhibits both Hsp90 inhibitory and immunogenic properties.
- The branching moieties of EnnA are essential for its observed activity.
- Certain structural modifications to EnnA were found to be tolerated without compromising activity.
Conclusions:
- Disrupting Hsp90 protein-protein interactions is a viable alternative to traditional inhibition.
- Enniatin A represents a novel class of Hsp90 inhibitors with potential therapeutic applications.
- Further SAR studies can guide the development of optimized EnnA analogs for cancer therapy.
More Related Videos
08:29Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
06:00Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
Published on: May 14, 2016
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:28Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists
02:39lncRNA - Long Non-coding RNAs