Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics.

To date, the most studied drug in anti-aging research is the mTOR inhibitor - rapamycin. Despite its almost perfect anti-aging profile, rapamycin exerts one significant limitation - inappropriate physicochemical properties. Therefore, we have decided to utilize virtual high-throughput screening and fragment-based design in search of novel mTOR inhibiting scaffolds with suitable physicochemical parameters. Seven lead compounds were selected from the list of obtained hits that were commercially available ( and ) or their synthesis was feasible ( and ) and evaluated and subsequently . Of all these substances, only compound demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound is a direct mTORC1 inhibitor. Last but not least, compound was found to exhibit anti-SASP activity concurrently being relatively safe within the test of tolerability. All these outstanding results highlight compound as a scaffold worthy of further investigation.