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

Suyoung Yoon, Jong Hyun Kim, Sung Eun Kim, Changhoon Kim, Phuong Thao Tran, Jihyae Ann, Yura Koh, Jayun Jang, Sungmin Kim, Hee Sun Moon, Won Kyung Kim, Sangkook Lee, Jiyoun Lee, Sunghoon Kim, Jeewoo Lee

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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.

Original languageEnglish
Pages (from-to)10322-10328
Number of pages7
JournalJournal of Medicinal Chemistry
Volume59
Issue number22
DOIs
Publication statusPublished - 2016 Nov 23

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Yoon, S., Kim, J. H., Kim, S. E., Kim, C., Tran, P. T., Ann, J., Koh, Y., Jang, J., Kim, S., Moon, H. S., Kim, W. K., Lee, S., Lee, J., Kim, S., & Lee, J. (2016). Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS)-Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors. Journal of Medicinal Chemistry, 59(22), 10322-10328. https://doi.org/10.1021/acs.jmedchem.6b01190