{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T12:28:11Z","timestamp":1777552091943,"version":"3.51.4"},"reference-count":23,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003715","name":"KRIBB","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003715","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003625","name":"Korea Ministry of Health and Welfare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003625","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Korea Ministry of Science ICT and Future Planning","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Bioorganic Chemistry"],"published-print":{"date-parts":[[2021,7]]},"DOI":"10.1016\/j.bioorg.2021.104907","type":"journal-article","created":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T20:37:01Z","timestamp":1618951021000},"page":"104907","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":11,"special_numbering":"C","title":["Structure-based modification of pyrazolone derivatives to inhibit mTORC1 by targeting the leucyl-tRNA synthetase-RagD interaction"],"prefix":"10.1016","volume":"112","author":[{"given":"Jae Hyun","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kilsoo","family":"Jung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chulho","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doona","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kibum","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hee Chan","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seung Joon","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jong Soon","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyeong-Ryoon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunghoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung Min","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyoonhee","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.bioorg.2021.104907_b0005","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1093\/mutage\/geu045","article-title":"The expanding role of mTOR in cancer cell growth and proliferation","volume":"30","author":"Cargnello","year":"2015","journal-title":"Mutagenesis"},{"key":"10.1016\/j.bioorg.2021.104907_b0010","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3233\/JAD-131124","article-title":"Differential activation of mTOR complex 1 signaling in human brain with mild to severe Alzheimer's disease","volume":"38","author":"Sun","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"10.1016\/j.bioorg.2021.104907_b0015","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1111\/j.1356-9597.2004.00727.x","article-title":"Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function","volume":"9","author":"Oshiro","year":"2004","journal-title":"Genes Cells"},{"key":"10.1016\/j.bioorg.2021.104907_b0020","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":"10.1016\/j.bioorg.2021.104907_b0025","doi-asserted-by":"crossref","first-page":"C1457","DOI":"10.1152\/ajpcell.00165.2005","article-title":"mTOR function in skeletal muscle hypertrophy: increased ribosomal RNA via cell cycle regulators","volume":"289","author":"Nader","year":"2005","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"10.1016\/j.bioorg.2021.104907_b0030","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1080\/08977190701779101","article-title":"Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function","volume":"25","author":"Jastrzebski","year":"2007","journal-title":"Growth Factors"},{"key":"10.1016\/j.bioorg.2021.104907_b0035","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.tcb.2014.03.003","article-title":"Regulation of mTORC1 by amino acids","volume":"24","author":"Bar-Peled","year":"2014","journal-title":"Trends Cell Biol."},{"key":"10.1016\/j.bioorg.2021.104907_b0040","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s12970-016-0118-y","article-title":"Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance","volume":"13","author":"Bond","year":"2016","journal-title":"J. Int. Soc. Sports Nutr."},{"key":"10.1016\/j.bioorg.2021.104907_b0045","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1126\/science.1157535","article-title":"The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1","volume":"320","author":"Sancak","year":"2008","journal-title":"Science"},{"key":"10.1016\/j.bioorg.2021.104907_b0050","doi-asserted-by":"crossref","first-page":"7246","DOI":"10.1074\/jbc.M004389200","article-title":"Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B","volume":"276","author":"Sekiguchi","year":"2001","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.bioorg.2021.104907_b0055","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.tibs.2005.08.004","article-title":"Functional expansion of aminoacyl-tRNA synthetases and their interacting factors: new perspectives on housekeepers","volume":"30","author":"Park","year":"2005","journal-title":"Trends Biochem. Sci."},{"key":"10.1016\/j.bioorg.2021.104907_b0060","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.cell.2012.02.044","article-title":"Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway","volume":"149","author":"Han","year":"2012","journal-title":"Cell"},{"key":"10.1016\/j.bioorg.2021.104907_b0065","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":"10.1016\/j.bioorg.2021.104907_b0070","doi-asserted-by":"crossref","first-page":"725","DOI":"10.4161\/auto.5.5.8504","article-title":"Rapamycin inhibits mTORC1, but not completely AU \u2013 Thoreen, Carson C","volume":"5","author":"Sabatini","year":"2009","journal-title":"Autophagy"},{"key":"10.1016\/j.bioorg.2021.104907_b0075","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/s41467-017-00785-0","article-title":"Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction","volume":"8","author":"Kim","year":"2017","journal-title":"Nat. Commun."},{"key":"10.1016\/j.bioorg.2021.104907_b0080","unstructured":"Dassault Syst\u00e8mes BIOVIA, D. S. M. E. R., Dassault Syst\u00e8mes. San Diego, 2020."},{"key":"10.1016\/j.bioorg.2021.104907_b0085","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S1359-6446(04)03365-3","article-title":"Predicting aqueous solubility from structure","volume":"10","author":"Delaney","year":"2005","journal-title":"Drug Discov. Today"},{"key":"10.1016\/j.bioorg.2021.104907_b0090","doi-asserted-by":"crossref","first-page":"5853","DOI":"10.1016\/j.bmc.2008.04.074","article-title":"High-throughput evaluation of relative cell permeability between peptoids and peptides","volume":"16","author":"Tan","year":"2008","journal-title":"Bioorg. Med. Chem."},{"issue":"4","key":"10.1016\/j.bioorg.2021.104907_b0095","first-page":"164","article-title":"The relation between molecular properties of drugs and their transport across the intestinal membrane","volume":"14","author":"Zakeri-Milani","year":"2006","journal-title":"DARU J. Pharm. Sci."},{"key":"10.1016\/j.bioorg.2021.104907_b0100","doi-asserted-by":"crossref","first-page":"E5279","DOI":"10.1073\/pnas.1801287115","article-title":"Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway","volume":"115","author":"Lee","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.bioorg.2021.104907_b0105","unstructured":"Bio Platform Technology Research Center, K. R. I. o. C. T., Daejeon 34114, South Korea."},{"issue":"5","key":"10.1016\/j.bioorg.2021.104907_b0110","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1172\/JCI122560","article-title":"Nontranslatsional function of leucyl-tRNA synthetase regulates myogenic differentiation and skeletal muscle regeneration","volume":"129","author":"Son","year":"2019","journal-title":"J. Clin. Invest."},{"issue":"8","key":"10.1016\/j.bioorg.2021.104907_b0115","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1093\/hmg\/ddaa068","article-title":"Klofas, Brittany P Short, Chengwen Zhou, Robert P Carson, Prevention of premature death and seizures in a Depdc5 mouse epilepsy model through inhibition of mTORC1","volume":"29","author":"Lindsay","year":"2020","journal-title":"Hum. Mol. Genet."}],"container-title":["Bioorganic Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0045206821002844?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0045206821002844?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T08:21:58Z","timestamp":1758615718000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0045206821002844"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7]]},"references-count":23,"alternative-id":["S0045206821002844"],"URL":"https:\/\/doi.org\/10.1016\/j.bioorg.2021.104907","relation":{},"ISSN":["0045-2068"],"issn-type":[{"value":"0045-2068","type":"print"}],"subject":[],"published":{"date-parts":[[2021,7]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Structure-based modification of pyrazolone derivatives to inhibit mTORC1 by targeting the leucyl-tRNA synthetase-RagD interaction","name":"articletitle","label":"Article Title"},{"value":"Bioorganic Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bioorg.2021.104907","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}],"article-number":"104907"}}