2. Academic Validation
  3. A Xanthine Derivative With Novel Heat Shock Protein 90-Alpha Inhibitory and Senolytic Properties

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

  • Aging Cell. 2025 Mar 17:e70047. doi: 10.1111/acel.70047.
Sandra Atlante 1 2,  Luca Cis 3,  Davide Pirolli 4,  Michela Gottardi Zamperla 1,  Veronica Barbi 1 3,  Antonello Mai 5,  Clemens Zwergel 5,  Serena Marcozzi 6,  Maria Elisa Giuliani 6,  Giorgia Bigossi 6,  Giovanni Lai 6,  Fiorenza Orlando 6,  Robertina Giacconi 6,  Fabrizia Lattanzio 7,  Giulia Matacchione 8,  Chiara Giordani 8,  Massimo Bracci 9,  Fabiola Olivieri 10 11,  Federico Boschi 12,  Paola Tabarelli De Fatis 13,  Giovanni Battista Ivaldi 13,  Marco Malavolta 6 11,  Antonella Farsetti 2,  Maria Cristina De Rosa 4,  Carlo Gaetano 1
Affiliations

Affiliations

  • 1 Laboratory of Epigenetics, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy.
  • 2 National Research Council (CNR)-IASI "A. Ruberti", Rome, Italy.
  • 3 Università Cattolica del Sacro Cuore, Rome, Italy.
  • 4 Institute of Chemical Sciences and Technologies "Giulio Natta" (SCITEC)-CNR, Rome, Italy.
  • 5 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
  • 6 Advanced Technology Center for Aging Research and Geriatric Mouse Clinic, IRCCS INRCA, Ancona, Italy.
  • 7 Scientific Direction, IRCCS INRCA, Ancona, Italy.
  • 8 Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy.
  • 9 Department of Clinical and Molecular Sciences, Occupational Medicine, Polytechnic University of Marche, Ancona, Italy.
  • 10 Advanced Technology Center for Aging Research, IRCCS INRCA, Ancona, Italy.
  • 11 Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica Delle Marche, Ancona, Italy.
  • 12 Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy.
  • 13 Department of Radiation Oncology, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy.
PMID: 40098059 DOI: 10.1111/acel.70047
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.

Keywords

drosophila; HSP90α inhibitors; aging; senescence; senolytics; xanthine.

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