التفاصيل البيبلوغرافية
| العنوان: |
Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics. |
| المؤلفون: |
Chrienova, Zofia, Rysanek, David, Oleksak, Patrik, Stary, Dorota, Bajda, Marek, Reinis, Milan, Mikyskova, Romana, Novotny, Ondrej, Andrys, Rudolf, Skarka, Adam, Vasicova, Pavla, Novak, Josef, Valis, Martin, Kuca, Kamil, Hodny, Zdenek, Nepovimova, Eugenie |
| المصدر: |
Frontiers in Aging Neuroscience; 12/6/2022, Vol. 14, p1-28, 28p |
| مصطلحات موضوعية: |
IN vitro studies, HIGH throughput screening (Drug development), FLOW cytometry, RAPAMYCIN, IN vivo studies, SPECTROPHOTOMETERS, GERIATRICS, MICROSCOPY, ANTINEOPLASTIC agents, MTOR inhibitors, NUCLEAR magnetic resonance spectroscopy, HEALTH outcome assessment, BIOINFORMATICS, AGING, MASS spectrometry, CELL proliferation, HISTOLOGICAL techniques, DESCRIPTIVE statistics, MOLECULAR structure, CELL lines, DATA analysis software, PHENOTYPES, THIN layer chromatography |
| مستخلص: |
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 fragmentbased 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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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