title: Discovery of (S)-4-isobutyloxazolidin-2-one as a novel leucyl-tRNA synthetase (LRS)-targeted mTORC1 inhibitor.
abstract: A series of leucinol analogs were investigated as leucyl-tRNA synthetase-targeted mTORC1 inhibitors. Among them, compound 5, (S)-4-isobutyloxazolidin-2-one, showed the most potent inhibition on the mTORC1 pathway in a concentration-dependent manner. Compound 5 inhibited downstream phosphorylation of mTORC1 by blocking leucine-sensing ability of LRS, without affecting the catalytic activity of LRS. In addition, compound 5 exhibited cytotoxicity against rapamycin-resistant colon cancer cells, suggesting that LRS has the potential to serve as a novel therapeutic target.
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Suyoung
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Ina
authors.initials: I
authors.lastname: Yoon
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Changhoon
authors.initials: C
authors.lastname: Kim
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Kim
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Yura
authors.initials: Y
authors.lastname: Koh
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Seung Jae
authors.initials: SJ
authors.lastname: Jeong
authors.affiliation: Department of Global Medical Science, Sungshin University, Seoul 142-732, Republic of Korea.
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: jeewoo@snu.ac.kr.
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D007533:Isoleucine-tRNA Ligase / Q000037:antagonists & inhibitors*; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013237:Stereoisomerism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D046912:Multiprotein Complexes; D023303:Oxazolidinones; C417575:leucinol; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D007533:Isoleucine-tRNA Ligase; D007930:Leucine; D020123:Sirolimus
keywords: Leucinol; Leucyl-tRNA synthetase; mTORC1 inhibitor