{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:25:45Z","timestamp":1790673945027,"version":"4.1.0"},"reference-count":107,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T00:00:00Z","timestamp":1660867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["ZR2019BB031"],"award-info":[{"award-number":["ZR2019BB031"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["ZR2020QB114"],"award-info":[{"award-number":["ZR2020QB114"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["81903780"],"award-info":[{"award-number":["81903780"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["82004233"],"award-info":[{"award-number":["82004233"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["ZR2019BB031"],"award-info":[{"award-number":["ZR2019BB031"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["ZR2020QB114"],"award-info":[{"award-number":["ZR2020QB114"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81903780"],"award-info":[{"award-number":["81903780"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82004233"],"award-info":[{"award-number":["82004233"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The mammalian target of rapamycin (mTOR) is a serine\/threonine kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family. The kinase exists in the forms of two complexes, mTORC1 and mTORC2, and it participates in cell growth, proliferation, metabolism, and survival. The kinase activity is closely related to the occurrence and development of multiple human diseases. Inhibitors of mTOR block critical pathways to produce antiviral, anti-inflammatory, antiproliferative and other effects, and they have been applied to research in cancer, inflammation, central nervous system diseases and viral infections. Existing mTOR inhibitors are commonly divided into mTOR allosteric inhibitors, ATP-competitive inhibitors and dual binding site inhibitors, according to their sites of action. In addition, there exist several dual-target mTOR inhibitors that target PI3K, histone deacetylases (HDAC) or ataxia telangiectasia mutated and Rad-3 related (ATR) kinases. This review focuses on the structure of mTOR protein and related signaling pathways as well as the structure and characteristics of various mTOR inhibitors. Non-rapalog allosteric inhibitors will open new directions for the development of new therapeutics specifically targeting mTORC1. The applications of ATP-competitive inhibitors in central nervous system diseases, viral infections and inflammation have laid the foundation for expanding the indications of mTOR inhibitors. Both dual-binding site inhibitors and dual-target inhibitors are beneficial in overcoming mTOR inhibitor resistance.<\/jats:p>","DOI":"10.3390\/molecules27165295","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T23:51:01Z","timestamp":1661125861000},"page":"5295","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":136,"title":["Overview of Research into mTOR Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"given":"Beibei","family":"Mao","sequence":"first","affiliation":[{"name":"College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3458-7754","authenticated-orcid":false,"given":"Li","family":"Ma","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Molecular Engineering, State Key Laboratory of Biobased Material and Green Papermaking, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3265-5442","authenticated-orcid":false,"given":"Dong-Sheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1955-4412","authenticated-orcid":false,"given":"Peizheng","family":"Yan","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1126\/science.270.5233.50","article-title":"PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints","volume":"270","author":"Keith","year":"1995","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/ncb1183","article-title":"Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive","volume":"6","author":"Jacinto","year":"2004","journal-title":"Nat. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.tips.2014.11.004","article-title":"Current treatment strategies for inhibiting mTOR in cancer","volume":"36","author":"Chiarini","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1517\/17460441.2013.800479","article-title":"Furthering the design and the discovery of small molecule ATP-competitive mTOR inhibitors as an effective cancer treatment","volume":"8","author":"Lv","year":"2013","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1101\/gad.887201","article-title":"Regulation of translation initiation by FRAP\/mTOR","volume":"15","author":"Gingras","year":"2001","journal-title":"Genes Dev."},{"key":"ref_7","first-page":"3504","article-title":"A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells","volume":"60","author":"Sekulic","year":"2000","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5857","DOI":"10.1021\/ja954328h","article-title":"X-ray crystal structure of 28-O-methylrapamycin complexed with FKBP12: Is the cyclohexyl moiety part of the effector domain of rapamycin?","volume":"118","author":"Kallen","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1126\/science.273.5272.239","article-title":"Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP","volume":"273","author":"Choi","year":"1996","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature12122","article-title":"mTOR kinase structure, mechanism and regulation","volume":"497","author":"Yang","year":"2013","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S1097-2765(03)00114-X","article-title":"G\u03b2L, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR","volume":"11","author":"Kim","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cell.2009.03.046","article-title":"DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival","volume":"137","author":"Peterson","year":"2009","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.molcel.2007.03.003","article-title":"PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase","volume":"25","author":"Sancak","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_14","first-page":"638","article-title":"mTOR signaling in tumorigenesis","volume":"1846","author":"Xu","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1093\/annonc\/mdi113","article-title":"mTOR-targeted therapy of cancer with rapamycin derivatives","volume":"16","author":"Vignot","year":"2005","journal-title":"Ann. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1158\/1078-0432.CCR-16-0623","article-title":"PI3K\/Akt\/mTOR signaling and plasma membrane proteins are implicated in responsiveness to adjuvant dendritic cell vaccination for metastatic colorectal cancer","volume":"23","author":"Qian","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/ERC-16-0324","article-title":"Targeting PI3K\/mTOR signaling exerts potent antitumor activity in pheochromocytoma in vivo","volume":"24","author":"Lee","year":"2017","journal-title":"Endocr. Relat. Cancer."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"33440","DOI":"10.18632\/oncotarget.7961","article-title":"PI3K\/Akt\/mTOR signaling pathway and targeted therapy for glioblastoma","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s11010-016-2853-4","article-title":"Akt\/AMPK\/mTOR pathway was involved in the autophagy induced by vitamin E succinate in human gastric cancer SGC-7901 cells","volume":"424","author":"Yu","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s11010-016-2868-x","article-title":"Induction of autophagy by salidroside through the AMPK-mTOR pathway protects vascular endothelial cells from oxidative stress-induced apoptosis","volume":"425","author":"Zheng","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.toxlet.2016.12.015","article-title":"4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K\/4EBP1 signaling by modulating AMPK activation in Sertoli cells","volume":"267","author":"Duan","year":"2017","journal-title":"Toxicol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1101\/gad.1256804","article-title":"Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1\/TSC2 tumor suppressor complex","volume":"18","author":"Brugarolas","year":"2004","journal-title":"Genes Dev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1101\/gad.1617608","article-title":"Hypoxia regulates TSC1\/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling","volume":"22","author":"DeYoung","year":"2008","journal-title":"Genes Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8204","DOI":"10.1073\/pnas.0502857102","article-title":"The coordinate regulation of the p53 and mTOR pathways in cells","volume":"102","author":"Feng","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S1097-2765(01)00323-9","article-title":"Regulation of PTEN transcription by p53","volume":"8","author":"Stambolic","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrm3522","article-title":"Amino acid signalling upstream of mTOR","volume":"14","author":"Jewell","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1126\/science.1259472","article-title":"Differential regulation of mTORC1 by leucine and glutamine","volume":"347","author":"Jewell","year":"2015","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1126\/science.1257132","article-title":"Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1","volume":"347","author":"Wang","year":"2015","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.bbamcr.2012.12.019","article-title":"Oestradiol signalling through the Akt-mTORC1-S6K1","volume":"1833","author":"Varea","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.celrep.2012.11.020","article-title":"S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1","volume":"3","author":"Denichenko","year":"2013","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"F583","DOI":"10.1152\/ajprenal.00357.2009","article-title":"The growing importance of mTORC1-S6K1 signaling in kidney","volume":"297","author":"Siroky","year":"2009","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1042\/BCJ20160845","article-title":"mTORC1 signalling and eIF4E\/4E-BP1 translation initiation factor stoichiometry influence recombinant protein productivity from GS-CHOK1 cells","volume":"473","author":"Josse","year":"2016","journal-title":"Biochem. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4","DOI":"10.12688\/f1000research.1-4.v1","article-title":"Rapamycin-insensitive mTORC1 activity controls eIF4E:4E-BP1 binding","volume":"1","author":"Livingstone","year":"2012","journal-title":"F1000Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1172\/JCI43008","article-title":"MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice","volume":"120","author":"Zhang","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1172\/JCI73939","article-title":"mTOR: A pharmacologic target for autophagy regulation","volume":"125","author":"Kim","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1172\/JCI73941","article-title":"The role for autophagy in cancer","volume":"125","author":"White","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15790","DOI":"10.1073\/pnas.1521919112","article-title":"mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy","volume":"112","author":"Zhao","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.cub.2004.06.054","article-title":"Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton","volume":"14","author":"Sarbassov","year":"2004","journal-title":"Curr. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1042\/BJ20102103","article-title":"Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney","volume":"436","author":"Pearce","year":"2011","journal-title":"Biochem. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation and regulation of Akt\/PKB by the rictor-mTOR complex","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1042\/BJ20081668","article-title":"mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1)","volume":"416","author":"Alessi","year":"2008","journal-title":"Biochem. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ddstr.2009.12.001","article-title":"mTOR mediated anti-cancer drug discovery","volume":"6","author":"Liu","year":"2009","journal-title":"Drug Discov. Today Ther. Strateg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1172\/JCI44145","article-title":"Next-generation mTOR inhibitors in clinical oncology: How pathway complexity informs therapeutic strategy","volume":"121","author":"Wander","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJMoa1109653","article-title":"Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer","volume":"366","author":"Baselga","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1586\/17512433.2013.827397","article-title":"Ridaforolimus in advanced or metastatic soft tissue and bone sarcomas","volume":"6","author":"Mita","year":"2013","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1021\/acs.jmedchem.1c00536","article-title":"In Silico and In Cell Hybrid Selection of Nonrapalog Ligands to Allosterically Inhibit the Kinase Activity of mTORC1","volume":"65","author":"Shams","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6232","DOI":"10.1158\/0008-5472.CAN-09-0299","article-title":"Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin","volume":"69","author":"Yu","year":"2009","journal-title":"Cancer. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3426","DOI":"10.1021\/jm200215y","article-title":"Potent, selective, and orally bioavailable inhibitors of mammalian target of rapamycin (mTOR) kinase based on a quaternary substituted dihydrofuropyrimidine","volume":"54","author":"Cohen","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"10958","DOI":"10.1021\/jm301389h","article-title":"Potent, selective, and orally bioavailable inhibitors of the mammalian target of rapamycin kinase domain exhibiting single agent antiproliferative activity","volume":"55","author":"Koehler","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1021\/ml3003132","article-title":"Discovery and biological profiling of potent and selective mTOR inhibitor GDC-0349","volume":"4","author":"Pei","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3090","DOI":"10.1021\/jm400194n","article-title":"Pyrimidoaminotropanes as potent, selective, and efficacious small molecule kinase inhibitors of the mammalian target of rapamycin (mTOR)","volume":"56","author":"Estrada","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5114","DOI":"10.1016\/j.bmcl.2012.05.104","article-title":"Conformationally-restricted cyclic sulfones as potent and selective mTOR kinase inhibitors","volume":"22","author":"Liu","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5950","DOI":"10.1016\/j.bmcl.2009.08.038","article-title":"The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase","volume":"19","author":"Malagu","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1016\/j.bmcl.2013.01.019","article-title":"Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014","volume":"23","author":"Pike","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"40002","DOI":"10.1074\/jbc.M111.297432","article-title":"Inhibition of mTOR kinase by AZD8055 can antagonize chemotherapy-induced cell death through autophagy induction and down-regulation of p62\/sequestosome 1","volume":"286","author":"Huang","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1158\/0008-5472.CAN-11-1780","article-title":"Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055)","volume":"72","author":"Holt","year":"2012","journal-title":"Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1042\/BST0390456","article-title":"Benefits of mTOR kinase targeting in oncology: Pre-clinical evidence with AZD8055","volume":"39","author":"Marshall","year":"2011","journal-title":"Biochem. Soc. Trans."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5097","DOI":"10.1016\/j.bmcl.2013.07.027","article-title":"A hit to lead discovery of novel N-methylated imidazolo-, pyrrolo-, and pyrazolo-pyrimidines as potent and selective mTOR inhibitors","volume":"23","author":"Lee","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4163","DOI":"10.1016\/j.bmcl.2012.04.036","article-title":"Sulfonyl-morpholino-pyrimidines: SAR and development of a novel class of selective mTOR kinase inhibitor","volume":"22","author":"Finlay","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2326","DOI":"10.1021\/jm501778s","article-title":"Discovery of AZD3147: A potent, selective dual inhibitor of mTORC1 and mTORC2","volume":"58","author":"Pike","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6746","DOI":"10.1016\/j.bmc.2014.11.003","article-title":"Design, synthesis, anticancer activity and docking studies of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives as mTOR inhibitors","volume":"22","author":"Zhu","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ejmech.2017.02.015","article-title":"Design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine derivatives as mTOR inhibitors","volume":"129","author":"Mao","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1021\/acsmedchemlett.6b00149","article-title":"CZ415, a highly selective mTOR inhibitor showing in vivo efficacy in a collagen induced arthritis model","volume":"7","author":"Cansfield","year":"2016","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8609","DOI":"10.1021\/acs.jmedchem.9b00972","article-title":"A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor","volume":"62","author":"Borsari","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6972","DOI":"10.1021\/acs.jmedchem.9b00348","article-title":"Discovery of 3-oxabicyclo[4.1.0]heptane, a non-nitrogen containing morpholine isostere, and its application in novel inhibitors of the PI3K-AKT-mTOR pathway","volume":"62","author":"Hobbs","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"10084","DOI":"10.1021\/acs.jmedchem.8b01262","article-title":"Discovery and preclinical characterization of 5-[4,6-bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a highly potent and selective mtorc1\/2 inhibitor for cancer and neurological disorders","volume":"61","author":"Rageot","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"13595","DOI":"10.1021\/acs.jmedchem.0c00620","article-title":"4-(Difluoromethyl)-5-(4-((3R,5S)-3,5-dimethylmorpholino)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)pyridin-2-amine (PQR626), a Potent, Orally Available, and Brain-Penetrant mTOR Inhibitor for the Treatment of Neurological Disorders","volume":"63","author":"Borsari","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1021\/acs.jmedchem.9b01398","article-title":"Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders","volume":"63","author":"Bonazzi","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"7146","DOI":"10.1021\/jm101144f","article-title":"Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer","volume":"53","author":"Liu","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8023","DOI":"10.1074\/jbc.M900301200","article-title":"An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1","volume":"284","author":"Thoreen","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1021\/jm101520v","article-title":"Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[H][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer","volume":"54","author":"Liu","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4237","DOI":"10.1016\/j.bmc.2015.06.046","article-title":"4-(N-Phenyl-N\u2032-substituted benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines as inhibitors of mammalian target of rapamycin","volume":"23","author":"Venkateswarlu","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"7585","DOI":"10.1016\/j.bmc.2015.11.003","article-title":"Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation","volume":"23","author":"Ma","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"13311","DOI":"10.1021\/ja205655w","article-title":"Discovery and assembly-line biosynthesis of the lymphostin pyrroloquinoline alkaloid family of mTOR inhibitors in Salinispora bacteria","volume":"133","author":"Miyanaga","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1021\/acs.jmedchem.7b01402","article-title":"Highly Selective, Potent, and Oral mTOR Inhibitor for Treatment of Cancer as Autophagy Inducer","volume":"61","author":"Guo","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.ejmech.2019.04.048","article-title":"Design, synthesis and pharmacological evaluation of a novel mTOR-targeted anti-EV71 agent","volume":"175","author":"Hao","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/nchembio.117","article-title":"Targeted polypharmacology: Discovery of dual inhibitors of tyrosine and phosphoinositide kinases","volume":"4","author":"Apsel","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1158\/1078-0432.CCR-13-2136","article-title":"The ATP-competitive mTOR inhibitor INK128 enhances in vitro and in vivo radiosensitivity of pancreatic carcinoma cells","volume":"20","author":"Hayman","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1158\/1541-7786.MCR-12-0605","article-title":"Equivalent benefit of rapamycin and a potent mTOR ATP-competitive inhibitor, MLN0128 (INK128), in a mouse model of tuberous sclerosis","volume":"11","author":"Guo","year":"2013","journal-title":"Mol. Cancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/leu.2012.276","article-title":"Efficacy of the investigational mTOR kinase inhibitor MLN0128\/INK128 in models of B-cell acute lymphoblastic leukemia","volume":"27","author":"Janes","year":"2013","journal-title":"Leukemia"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1016\/j.bmcl.2011.01.139","article-title":"Imidazo[1,5-a]pyrazines: Orally efficacious inhibitors of mTORC1 and mTORC2","volume":"21","author":"Crew","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1158\/1535-7163.MCT-10-1099","article-title":"Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: Distinct from rapamycin","volume":"10","author":"Bhagwat","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_83","first-page":"638","article-title":"Novel inhibitors of mTORC1 and mTORC2","volume":"11","author":"Bhagwat","year":"2010","journal-title":"Curr. Opin. Investig. Drugs."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1021\/jm3007933","article-title":"Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR)","volume":"56","author":"Takeuchi","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4967","DOI":"10.1016\/j.bmcl.2012.06.033","article-title":"Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors","volume":"22","author":"Peterson","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1016\/j.bmcl.2013.01.110","article-title":"Use of core modification in the discovery of CC214-2, an orally available, selective inhibitor of mTOR kinase","volume":"23","author":"Mortensen","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"5323","DOI":"10.1021\/acs.jmedchem.5b00626","article-title":"Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223","volume":"58","author":"Mortensen","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5599","DOI":"10.1021\/acs.jmedchem.5b00627","article-title":"Optimization of a series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors and the discovery of CC-115","volume":"58","author":"Mortensen","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.ejmech.2014.04.051","article-title":"Synthesis of 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one analogs and their biological evaluation as anticancer agents: mTOR inhibitors","volume":"80","author":"Reddy","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"6559","DOI":"10.1021\/acs.jmedchem.5b00991","article-title":"A novel covalent mTOR inhibitor, DHM25, shows in vivo antitumor activity against triple-negative breast cancer cells","volume":"58","author":"Fouque","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"113424","DOI":"10.1016\/j.ejmech.2021.113424","article-title":"Identification and optimization of 3-bromo-N\u2019-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives as mTOR inhibitors that induce autophagic cell death and apoptosis in triple-negative breast cancer","volume":"219","author":"Xu","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"126659","DOI":"10.1016\/j.bmcl.2019.126659","article-title":"Rational discovery of a highly novel and selective mTOR inhibitor","volume":"29","author":"Jin","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nature17963","article-title":"Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor","volume":"534","author":"Okaniwa","year":"2016","journal-title":"Nature"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"8022","DOI":"10.1158\/0008-5472.CAN-08-1385","article-title":"NVP-BEZ235, a dual PI3K\/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations","volume":"68","author":"Serra","year":"2008","journal-title":"Cancer Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1021\/jm901830p","article-title":"Bis(morpholino-1,3,5-triazine) derivatives: Potent adenosine 5\u2032-triphosphate competitive phosphatidylinositol-3-kinase\/mammalian target of rapamycin inhibitors: Discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor","volume":"58","author":"Venkatesan","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1159\/000448843","article-title":"Inhibition of mTOR\u2019s catalytic site by PKI-587 is a promising therapeutic option for gastroenteropancreatic neuroendocrine tumor disease","volume":"105","author":"Freitag","year":"2017","journal-title":"Neuroendocrinology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1021\/ml900028r","article-title":"Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin","volume":"1","author":"Knight","year":"2010","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"7579","DOI":"10.1021\/jm2009327","article-title":"Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)\/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer","volume":"54","author":"Sutherlin","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"7524","DOI":"10.1021\/acs.jmedchem.7b00930","article-title":"5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a potent, brain-penetrant, orally bioavailable, pan-class I PI3K\/mTOR inhibitor as clinical candidate in oncology","volume":"60","author":"Beaufils","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1868-7083-4-5","article-title":"Roles of histone deacetylases in epigenetic regulation: Emerging paradigms from studies with inhibitors","volume":"4","author":"Delcuve","year":"2012","journal-title":"Clin. Epigenet."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Rehan, M. (2019). Anticancer compound XL765 as PI3K\/mTOR dual inhibitor: A structural insight into the inhibitory mechanism using computational approaches. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0219180"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S2352-3026(18)30030-9","article-title":"Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: An open-label, phase 2 trial","volume":"5","author":"Brown","year":"2018","journal-title":"Lancet Haematol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1021\/acs.jmedchem.8b01825","article-title":"Discovery of Novel Dual Histone Deacetylase and Mammalian Target of Rapamycin Target Inhibitors as a Promising Strategy for Cancer Therapy","volume":"62","author":"Chen","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"128204","DOI":"10.1016\/j.bmcl.2021.128204","article-title":"Design, synthesis and biological evaluation of dual mTOR\/HDAC6 inhibitors in MDA-MB-231 cells","volume":"47","author":"Yao","year":"2021","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"128286","DOI":"10.1016\/j.bmcl.2021.128286","article-title":"Discovery of novel pyrazolopyrimidine derivatives as potent mTOR\/HDAC bi-functional inhibitors via pharmacophore-merging strategy","volume":"49","author":"Zhang","year":"2021","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"113824","DOI":"10.1016\/j.ejmech.2021.113824","article-title":"Design, synthesis and biological evaluation of novel hybrids targeting mTOR and HDACs for potential treatment of hepatocellular carcinoma","volume":"225","author":"Zhai","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"127517","DOI":"10.1016\/j.bmcl.2020.127517","article-title":"Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor","volume":"30","author":"Bhakuni","year":"2020","journal-title":"Bioorg. Med. Chem. Lett."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/16\/5295\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:12:22Z","timestamp":1760141542000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/16\/5295"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,19]]},"references-count":107,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["molecules27165295"],"URL":"https:\/\/doi.org\/10.3390\/molecules27165295","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,19]]}}}