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Identification of the first-in-class dual inhibitor targeting BAG3 and HSP70 proteins to disrupt multiple chaperone pathways
D. Ruggiero, E. Ingenito, E. Boccia, V. Vestuto, G. D'Urso, A. Capuano, A. Casapullo, S. Terracciano, G. Bifulco, G. Lauro, I. Bruno
Language English Country France
Document type Journal Article
- MeSH
- Adaptor Proteins, Signal Transducing * metabolism antagonists & inhibitors MeSH
- Humans MeSH
- Molecular Chaperones metabolism antagonists & inhibitors chemistry MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Apoptosis Regulatory Proteins * metabolism antagonists & inhibitors MeSH
- HSP70 Heat-Shock Proteins * antagonists & inhibitors metabolism MeSH
- Antineoplastic Agents * pharmacology chemistry chemical synthesis MeSH
- Drug Screening Assays, Antitumor MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
In the complex network of cellular physiology, the maintenance of cellular proteostasis emerges as a critical factor for cell survival, particularly under stress conditions. This homeostasis is largely governed by a sophisticated network of molecular chaperones and co-chaperones, among which Bcl-2-associated athanogene 3 (BAG3), able to interact with the ATPase domain of Heat Shock Protein 70 (HSP70), plays a pivotal role. The BAG3-HSP70 functional module is not only essential for cellular homeostasis but is also involved in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, and cardiac dysfunction, making it an attractive target for therapeutic intervention. Inspired by our continuous interest in the development of new chemical platforms able to interfere with BAG3 protein, herein we report the discovery of compound 16, the first-in-class BAG3/HSP70 dual modulator, obtained by combining the multicomponent Ugi reaction with the alkyne-azide Huisgen procedure in a sequential tandem reaction approach. Through a combination of biophysical analysis, biochemical assays, and cell-based studies, we elucidated the mechanism of action of this inhibitor and assessed its potential as a therapeutic agent. Hence, this study can open new avenues for the development of novel anticancer strategies that leverage the simultaneous disruption of multiple chaperone pathways.
References provided by Crossref.org
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- $a Ruggiero, Dafne $u Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: druggiero@unisa.it
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- $a In the complex network of cellular physiology, the maintenance of cellular proteostasis emerges as a critical factor for cell survival, particularly under stress conditions. This homeostasis is largely governed by a sophisticated network of molecular chaperones and co-chaperones, among which Bcl-2-associated athanogene 3 (BAG3), able to interact with the ATPase domain of Heat Shock Protein 70 (HSP70), plays a pivotal role. The BAG3-HSP70 functional module is not only essential for cellular homeostasis but is also involved in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, and cardiac dysfunction, making it an attractive target for therapeutic intervention. Inspired by our continuous interest in the development of new chemical platforms able to interfere with BAG3 protein, herein we report the discovery of compound 16, the first-in-class BAG3/HSP70 dual modulator, obtained by combining the multicomponent Ugi reaction with the alkyne-azide Huisgen procedure in a sequential tandem reaction approach. Through a combination of biophysical analysis, biochemical assays, and cell-based studies, we elucidated the mechanism of action of this inhibitor and assessed its potential as a therapeutic agent. Hence, this study can open new avenues for the development of novel anticancer strategies that leverage the simultaneous disruption of multiple chaperone pathways.
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