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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2022.1048260/full |
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| author | Zofia Chrienova David Rysanek Patrik Oleksak Dorota Stary Dorota Stary Marek Bajda Milan Reinis Romana Mikyskova Ondrej Novotny Rudolf Andrys Adam Skarka Pavla Vasicova Josef Novak Martin Valis Martin Valis Kamil Kuca Zdenek Hodny Eugenie Nepovimova |
| author_facet | Zofia Chrienova David Rysanek Patrik Oleksak Dorota Stary Dorota Stary Marek Bajda Milan Reinis Romana Mikyskova Ondrej Novotny Rudolf Andrys Adam Skarka Pavla Vasicova Josef Novak Martin Valis Martin Valis Kamil Kuca Zdenek Hodny Eugenie Nepovimova |
| author_sort | Zofia Chrienova |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T13:38:20Z |
| format | Article |
| id | doaj.art-2138141c119d4080852852773bb5684e |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-04-11T13:38:20Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-2138141c119d4080852852773bb5684e2022-12-22T04:21:21ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652022-12-011410.3389/fnagi.2022.10482601048260Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeuticsZofia Chrienova0David Rysanek1Patrik Oleksak2Dorota Stary3Dorota Stary4Marek Bajda5Milan Reinis6Romana Mikyskova7Ondrej Novotny8Rudolf Andrys9Adam Skarka10Pavla Vasicova11Josef Novak12Martin Valis13Martin Valis14Kamil Kuca15Zdenek Hodny16Eugenie Nepovimova17Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, CzechiaDepartment of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, CzechiaDepartment of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, CzechiaDepartment of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, PolandDoctoral School of Medical and Health Sciences, Jagiellonian University Medical College, Kraków, PolandDepartment of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, PolandLaboratory of Immunological and Tumor Models, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, CzechiaLaboratory of Immunological and Tumor Models, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, CzechiaLaboratory of Immunological and Tumor Models, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, CzechiaDepartment of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, CzechiaDepartment of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, CzechiaDepartment of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, CzechiaDepartment of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, CzechiaDepartment of Neurology, University Hospital Hradec Kralove, Hradec Králové, CzechiaFaculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, CzechiaDepartment of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, CzechiaDepartment of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, CzechiaDepartment of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, CzechiaTo 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.https://www.frontiersin.org/articles/10.3389/fnagi.2022.1048260/fullagingcancermTORanti-aging therapySASP phenotype |
| spellingShingle | Zofia Chrienova David Rysanek Patrik Oleksak Dorota Stary Dorota Stary Marek Bajda Milan Reinis Romana Mikyskova Ondrej Novotny Rudolf Andrys Adam Skarka Pavla Vasicova Josef Novak Martin Valis Martin Valis Kamil Kuca Zdenek Hodny Eugenie Nepovimova Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics Frontiers in Aging Neuroscience aging cancer mTOR anti-aging therapy SASP phenotype |
| title | Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics |
| title_full | Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics |
| title_fullStr | Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics |
| title_full_unstemmed | Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics |
| title_short | Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics |
| title_sort | discovery of small molecule mechanistic target of rapamycin inhibitors as anti aging and anti cancer therapeutics |
| topic | aging cancer mTOR anti-aging therapy SASP phenotype |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2022.1048260/full |
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