Discovery of (S)-4-isobutyloxazolidin-2-one as a novel leucyl-tRNA synthetase (LRS)-targeted mTORC1 inhibitor. Issue 13 (1st July 2016)

• Record Type: Journal Article
• Authors: Yoon, Suyoung; Kim, Jong Hyun; Yoon, Ina; Kim, Changhoon; Kim, Sung-Eun; Koh, Yura; Jeong, Seung Jae; Lee, Jiyoun; Kim, Sunghoon; Lee, Jeewoo
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 13(2016)
• Page Start: 3038
• Page End: 3041
• Publication Date: 2016-07-01
• Subjects: Leucyl-tRNA synthetase -- mTORC1 inhibitor -- Leucinol; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.05.011
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of leucinol analogs were investigated as leucyl-tRNA synthetase-targeted mTORC1 inhibitors. Among them, compound5, ( S )-4-isobutyloxazolidin-2-one, showed the most potent inhibition on the mTORC1 pathway in a concentration-dependent manner. Compound5 inhibited downstream phosphorylation of mTORC1 by blocking leucine-sensing ability of LRS, without affecting the catalytic activity of LRS. In addition, compound5 exhibited cytotoxicity against rapamycin-resistant colon cancer cells, suggesting that LRS has the potential to serve as a novel therapeutic target.