A Xanthine Derivative With Novel Heat Shock Protein 90‐Alpha Inhibitory and Senolytic Properties

The accumulation of senescent cells contributes to aging and related diseases; therefore, discovering safe senolytic agents-compounds that selectively eliminate senescent cells-is a critical priority. Heat shock protein 90 (HSP90) inhibitors (HSP90i), traditionally investigated for cancer treatment, have shown potential as senolytic agents. However, inhibitors face formulation, toxicity, and cost challenges. To overcome these limitations, we employed a virtual screening approach combining structure-based prefiltering with a ligand-based pharmacophore model to identify novel, potentially safe HSP90 alpha isoform inhibitors exhibiting senolytic properties. This strategy identified 14 candidate molecules evaluated for senolytic activity in primary human fetal pulmonary fibroblasts. Four compounds exhibited significant HSP90i and senolytic activity, including two novel compounds, namely K4 and K5. The latter, 1-benzyl-3-(2-methylphenyl)-3,7-dihydro-1H-purine-2,6-dione, structurally related to the xanthinic family, emerged as a promising, well-tolerated senolytic agent. K5 demonstrated senolytic activity across various cellular senescence models, including human fibroblasts, mesenchymal stem cells, and breast cancer cells. It was also effective in vivo, extending lifespan in Drosophila and reducing senescence markers in geriatric mice. Additionally, the xanthinic nature of K5 implicates a multimodal action, now including the inhibition of HSP90α, that might enhance its efficacy and selectivity towards senescent cells, Senolytic index SI > 1320 for IMR90 cells, and SI > 770 for WI38 cells, underscoring its therapeutic potential. These findings advance senolytic therapy research, opening new avenues for safer interventions to combat age-related inflammaging and diseases, including cancer, and possibly extend a healthy lifespan.

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Publication Details

Journal
Aging Cell
Published
2025-03-17
DOI
https://doi.org/10.1111/acel.70047
Citations
2
Primary Topic
Telomeres, Telomerase, and Senescence
Type
article
Field-Weighted Citation Impact
2.33

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article

A Xanthine Derivative With Novel Heat Shock Protein 90‐Alpha Inhibitory and Senolytic Properties

Antonella Farsetti, Massimo Bracci, Fiorenza Orlando, Antonello Mai et al.
2 citations
Aging Cell
Telomeres, Telomerase, and Senescence
2.33
article

A Xanthine Derivative With Novel Heat Shock Protein 90‐Alpha Inhibitory and Senolytic Properties

Antonella Farsetti, Massimo Bracci, Fiorenza Orlando, Antonello Mai, Fabrizia Lattanzio, Marco Malavolta, Chiara Giordani, Michela Gottardi Zamperla, Clemens Zwergel, Giovanni Lai, Maria Elisa Giuliani, Robertina Giacconi, Luca Cis, Paola Tabarelli de Fatis, Olivieri Fabiola, Davide Pirolli, Maria Cristina De Rosa, Gilles Ivaldi, Sandra Atlante, Serena Marcozzi, Veronica Barbi, Giulia Matacchione, Giorgia Bigossi, Carlo Gaetano, Federico Boschi
article en
2 citations

Abstract

The accumulation of senescent cells contributes to aging and related diseases; therefore, discovering safe senolytic agents-compounds that selectively eliminate senescent cells-is a critical priority. Heat shock protein 90 (HSP90) inhibitors (HSP90i), traditionally investigated for cancer treatment, have shown potential as senolytic agents. However, inhibitors face formulation, toxicity, and cost challenges. To overcome these limitations, we employed a virtual screening approach combining structure-based prefiltering with a ligand-based pharmacophore model to identify novel, potentially safe HSP90 alpha isoform inhibitors exhibiting senolytic properties. This strategy identified 14 candidate molecules evaluated for senolytic activity in primary human fetal pulmonary fibroblasts. Four compounds exhibited significant HSP90i and senolytic activity, including two novel compounds, namely K4 and K5. The latter, 1-benzyl-3-(2-methylphenyl)-3,7-dihydro-1H-purine-2,6-dione, structurally related to the xanthinic family, emerged as a promising, well-tolerated senolytic agent. K5 demonstrated senolytic activity across various cellular senescence models, including human fibroblasts, mesenchymal stem cells, and breast cancer cells. It was also effective in vivo, extending lifespan in Drosophila and reducing senescence markers in geriatric mice. Additionally, the xanthinic nature of K5 implicates a multimodal action, now including the inhibition of HSP90α, that might enhance its efficacy and selectivity towards senescent cells, Senolytic index SI > 1320 for IMR90 cells, and SI > 770 for WI38 cells, underscoring its therapeutic potential. These findings advance senolytic therapy research, opening new avenues for safer interventions to combat age-related inflammaging and diseases, including cancer, and possibly extend a healthy lifespan.

Aging CellVol. 24(7)
Università Cattolica del Sacro Cuore (IT), University of Verona (IT), Marche Polytechnic University (IT), Istituti Clinici Scientifici Maugeri (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), National Research Council (IT), Istituto Nazionale di Riposo e Cura per Anziani (IT), Sapienza University of Rome (IT)
Ministero della Salute, Consiglio Nazionale delle Ricerche
Good health and well-being
Openalex Percentile: Top 14%
Telomeres, Telomerase, and Senescence
2.33
DOIOpen Access PDFOpenAlex
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