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

Area of Science:

• Gerontology
• Molecular Biology
• Pharmacology

Background:

• Cellular senescence drives aging and age-related diseases.
• Heat Shock Protein 90 (HSP90) inhibitors show senolytic potential but face challenges.
• Novel, safe senolytic agents are critical for therapeutic interventions.

Purpose of the Study:

• To identify novel, safe Heat Shock Protein 90 alpha (HSP90α) inhibitors with senolytic properties.
• To overcome limitations of existing HSP90 inhibitors through virtual screening.
• To evaluate the senolytic efficacy and safety of identified compounds.

Main Methods:

• Employed virtual screening combining structure-based and ligand-based pharmacophore modeling.
• Identified 14 candidate HSP90α inhibitors.
• Evaluated senolytic activity in primary human fetal pulmonary fibroblasts, various cell models, and in vivo studies.

Main Results:

• Four compounds exhibited significant HSP90 inhibition and senolytic activity.
• Novel compounds K4 and K5 were identified, with K5 showing particular promise.
• K5 demonstrated broad senolytic activity in vitro, extended lifespan in Drosophila, and reduced senescence markers in mice.

Conclusions:

• K5, a xanthinic compound, is a potent, well-tolerated senolytic agent targeting HSP90α.
• K5 exhibits multimodal action, enhancing selectivity and efficacy against senescent cells.
• Findings offer new avenues for safer senolytic therapies against aging, inflammaging, and cancer.