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

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

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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