title: Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS)-Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors.
abstract: Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound 18 selectively inhibited LRS-mediated mTORC1 activation and exerted specific cytotoxicity against colon cancer cells with a hyperactive mTORC1, suggesting that 18 may offer a novel treatment option for human colorectal cancer.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, 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, Korea.
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Changhoon
authors.initials: C
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Phuong-Thao
authors.initials: PT
authors.lastname: Tran
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Jihyae
authors.initials: J
authors.lastname: Ann
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, 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, Korea.
authors.forename: Jayun
authors.initials: J
authors.lastname: Jang
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Sungmin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Moon
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Won Kyung
authors.initials: WK
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Sangkook
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Global Medical Science, Sungshin University , Seoul 142-732, 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, Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University , Seoul 151-742, Korea.
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007935:Leucine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D015394:Molecular Structure; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D046912:Multiprotein Complexes; C000620282:leucyladenylate sulfamate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D007935:Leucine-tRNA Ligase; D007930:Leucine