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 (4, 5, and 7) or their synthesis was feasible (1, 2, 3, and 6) and evaluated in vitro and subsequently in vivo. Of all these substances, only compound 3 demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound 3 is a direct mTORC1 inhibitor. Last but not least, compound 3 was found to exhibit anti-SASP activity concurrently being relatively safe within the test of in vivo tolerability. All these outstanding results highlight compound 3 as a scaffold worthy of further investigation.

Department of Chemistry Faculty of Science University of Hradec Králové Hradec Králové Czechia

Department of Genome Integrity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czechia

Department of Neurology University Hospital Hradec Kralove Hradec Králové Czechia

Department of Physicochemical Drug Analysis Faculty of Pharmacy Jagiellonian University Medical College Kraków Poland

Doctoral School of Medical and Health Sciences Jagiellonian University Medical College Kraków Poland

Faculty of Medicine in Hradec Králové Charles University Prague Hradec Králové Czechia

Laboratory of Immunological and Tumor Models Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czechia

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Discovery of a 6-Aminobenzo[b]thiophene 1,1-Dioxide Derivative (K2071) with a Signal Transducer and Activator of Transcription 3 Inhibitory, Antimitotic, and Senotherapeutic Activities