Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS)-Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors

  • J Med Chem. 2016 Nov 23;59(22):10322-10328. doi: 10.1021/acs.jmedchem.6b01190.
Suyoung Yoon  1 ,  Jong Hyun Kim  2 ,  Sung-Eun Kim  1 ,  Changhoon Kim  1 ,  Phuong-Thao Tran  1 ,  Jihyae Ann  1 ,  Yura Koh  1 ,  Jayun Jang  2 ,  Sungmin Kim  2 ,  Hee-Sun Moon  2 ,  Won Kyung Kim  1 ,  Sangkook Lee  1 ,  Jiyoun Lee  3 ,  Sunghoon Kim  2  4 ,  Jeewoo Lee  1
Affiliations
  • 1. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
  • 2. Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
  • 3. Department of Global Medical Science, Sungshin University , Seoul 142-732, Korea.
  • 4. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University , Seoul 151-742, Korea.
PMID: 27933890 DOI: 10.1021/acs.jmedchem.6b01190
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.

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