2. Academic Validation
  3. Identification of the first-in-class dual inhibitor targeting BAG3 and HSP70 proteins to disrupt multiple chaperone pathways

Identification of the first-in-class dual inhibitor targeting BAG3 and HSP70 proteins to disrupt multiple chaperone pathways

  • Eur J Med Chem. 2025 Apr 5:287:117358. doi: 10.1016/j.ejmech.2025.117358.
Dafne Ruggiero 1,  Emis Ingenito 2,  Eleonora Boccia 3,  Vincenzo Vestuto 4,  Gilda D'Urso 5,  Alessandra Capuano 6,  Agostino Casapullo 7,  Stefania Terracciano 8,  Giuseppe Bifulco 9,  Gianluigi Lauro 10,  Ines Bruno 11
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: druggiero@unisa.it.
  • 2 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry and Czech Advanced Technology and Research Institute, Palackу University in Olomouc, Krížkovského 511/8, 779 00, Olomouc, Czech Republic. Electronic address: eingenito@unisa.it.
  • 3 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: eboccia@unisa.it.
  • 4 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: vvestuto@unisa.it.
  • 5 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: gidurso@unisa.it.
  • 6 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: acapuano@unisa.it.
  • 7 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: casapullo@unisa.it.
  • 8 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: sterracciano@unisa.it.
  • 9 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: bifulco@unisa.it.
  • 10 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: glauro@unisa.it.
  • 11 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. Electronic address: brunoin@unisa.it.
PMID: 39947053 DOI: 10.1016/j.ejmech.2025.117358
Abstract

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.

Keywords

Anticancer agent; BAG3; Dual modulator; HSP70; Ugi-Huisgen tandem approach.

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