With the advent of senolytic agents, capable of selectively removing senescent cells in “aged” tissues, the perception of age-associated diseases has changed from being an inevitable to a preventable phenomenon of human life. The present invention is part of this research topic with the identification of molecules with potential pro-apoptotic activity, specifically with senolytic activity. The computational approach adopted, is based on combining ligand-base and structure-based virtual screening. The in vitro assays have been carried out by developing a senescence model through serial passages of primary human fetal lung cells IMR90. In particular, 14 molecules, identified by virtual screening, revealed a higher, lower or absent pro-apoptotic activity in senescent cells and no effect in cell populations with lower number of passages. Of this series, two compounds revealed a marked senolytic capacity in vitro, reducing the aging population by about 50% in the first 48 hours of exposure to the drug. The compounds are now under evaluation in vivo, in an aging modelcarried out in mice older than 24 months.
The molecules of interest fall within the topic of senolytic agents, ie compounds that kill the senescent cells within living organisms. Other senolytic agents are known in the literature which share the putative molecular target of the molecules considered in this invention, namely the Heat shock protein 90 (HSP90). The molecules we have identified as potential senolytic drugs have the advantage of selectively promoting programmed death (apoptosis) and the inhibition of replication potential in the cellular senescence model adopted. They also showed reduced toxicity when compared with known compounds, using in vitro models. We have begun in vivo studies and will soon have information about the toxicity and efficacy of the compounds of interest in an aging model carried out in mice.
Italy