{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Chrienova Z"],"funding":["Ministerstvo Zdravotnictví Ceské Republiky","Univerzita Karlova v Praze","Grantová Agentura České Republiky","Univerzita Hradec Králové"],"pagination":["1048260"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9767416"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["14"],"pubmed_abstract":["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 (<b>4, 5,</b> and <b>7</b>) or their synthesis was feasible (<b>1, 2, 3,</b> and <b>6</b>) and evaluated <i>in vitro</i> and subsequently <i>in vivo</i>. Of all these substances, only compound <b>3</b> demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound <b>3</b> is a direct mTORC1 inhibitor. Last but not least, compound <b>3</b> was found to exhibit anti-SASP activity concurrently being relatively safe within the test of <i>in vivo</i> tolerability. All these outstanding results highlight compound <b>3</b> as a scaffold worthy of further investigation."],"journal":["Frontiers in aging neuroscience"],"pubmed_title":["Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics."],"pmcid":["PMC9767416"],"funding_grant_id":["UHHK, 00179906","PROGRES Q40/15","SV2104-2021","20-22037S","RVO 68378050","VT2019-2021"],"pubmed_authors":["Oleksak P","Mikyskova R","Stary D","Rysanek D","Kuca K","Chrienova Z","Reinis M","Nepovimova E","Novotny O","Bajda M","Novak J","Valis M","Andrys R","Skarka A","Vasicova P","Hodny Z"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics.","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 (<b>4, 5,</b> and <b>7</b>) or their synthesis was feasible (<b>1, 2, 3,</b> and <b>6</b>) and evaluated <i>in vitro</i> and subsequently <i>in vivo</i>. Of all these substances, only compound <b>3</b> demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound <b>3</b> is a direct mTORC1 inhibitor. Last but not least, compound <b>3</b> was found to exhibit anti-SASP activity concurrently being relatively safe within the test of <i>in vivo</i> tolerability. All these outstanding results highlight compound <b>3</b> as a scaffold worthy of further investigation.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022","modification":"2024-11-20T11:21:03.645Z","creation":"2024-11-20T11:21:03.645Z"},"accession":"S-EPMC9767416","cross_references":{"pubmed":["36561137"],"doi":["10.3389/fnagi.2022.1048260"]}}