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Importantly, rapamycin analogues (rapalogs) are of clinical importance against certain cancer types and neurodevelopmental diseases. Although rapamycin is widely perceived as an allosteric inhibitor of mTOR (mechanistic target of rapamycin), the master regulator of cellular and organismal physiology, its specificity has not been thoroughly evaluated so far. In fact, previous studies in cells and in mice hinted that rapamycin may be also acting independently from mTOR to influence various cellular processes. Here, we generated a gene\u2010edited cell line that expresses a rapamycin\u2010resistant mTOR mutant (mTOR<jats:sup>RR<\/jats:sup>) and assessed the effects of rapamycin treatment on the transcriptome and proteome of control or mTOR<jats:sup>RR<\/jats:sup>\u2010expressing cells. Our data reveal a striking specificity of rapamycin towards mTOR, demonstrated by virtually no changes in mRNA or protein levels in rapamycin\u2010treated mTOR<jats:sup>RR<\/jats:sup> cells, even following prolonged drug treatment. Overall, this study provides the first unbiased and conclusive assessment of rapamycin's specificity, with potential implications for ageing research and human therapeutics.<\/jats:p>","DOI":"10.1111\/acel.13888","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T07:46:36Z","timestamp":1684914396000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Unbiased evaluation of rapamycin's specificity as an <scp>mTOR<\/scp> inhibitor"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3902-9217","authenticated-orcid":false,"given":"Filippo","family":"Artoni","sequence":"first","affiliation":[{"name":"Max Planck Institute for Biology of Ageing (MPI\u2010AGE)  Cologne Germany"},{"name":"Cologne Graduate School of Ageing Research (CGA)  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Gr\u00fctzmacher","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Biology of Ageing (MPI\u2010AGE)  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7813-7726","authenticated-orcid":false,"given":"Constantinos","family":"Demetriades","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Biology of Ageing (MPI\u2010AGE)  Cologne Germany"},{"name":"Cologne Graduate School of Ageing Research (CGA)  Cologne Germany"},{"name":"Cologne Excellence Cluster on Cellular Stress Responses in Aging\u2010Associated Diseases (CECAD) University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,5,24]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glw090"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92893"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20021535"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20070797"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.10.001"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3531"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.16351"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.11.010"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.06.013"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/377441a0"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3540413"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1913212116"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.11.4947"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.3044"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5272.239"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092\u20108674(92)90643\u2010q"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1511"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201004282\u20109"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1042\/0264\u20106021:3510095"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1990"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.01.024"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3945\/jn.111.139485"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1130276"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1187532"},{"key":"e_1_2_11_26_1","unstructured":"EMA. 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