Discovery of (S)-4-isobutyloxazolidin-2-one as a novel leucyl-tRNA synthetase (LRS)-targeted mTORC1 inhibitor

Suyoung Yoon; Jong Hyun Kim; Ina Yoon; Changhoon Kim; Sung-Eun Kim; Yura Koh; Seung Jae Jeong; Jiyoun Lee; Sunghoon Kim; Jeewoo Lee

doi:10.1016/j.bmcl.2016.05.011

Discovery of (S)-4-isobutyloxazolidin-2-one as a novel leucyl-tRNA synthetase (LRS)-targeted mTORC1 inhibitor

Bioorg Med Chem Lett. 2016 Jul 1;26(13):3038-3041. doi: 10.1016/j.bmcl.2016.05.011. Epub 2016 May 7.

Authors

Affiliations

¹ Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
² Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
³ Department of Global Medical Science, Sungshin University, Seoul 142-732, Republic of Korea.
⁴ Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, Republic of Korea.
⁵ Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: jeewoo@snu.ac.kr.

PMID: 27209231
DOI: 10.1016/j.bmcl.2016.05.011

Abstract

A series of leucinol analogs were investigated as leucyl-tRNA synthetase-targeted mTORC1 inhibitors. Among them, compound 5, (S)-4-isobutyloxazolidin-2-one, showed the most potent inhibition on the mTORC1 pathway in a concentration-dependent manner. Compound 5 inhibited downstream phosphorylation of mTORC1 by blocking leucine-sensing ability of LRS, without affecting the catalytic activity of LRS. In addition, compound 5 exhibited cytotoxicity against rapamycin-resistant colon cancer cells, suggesting that LRS has the potential to serve as a novel therapeutic target.

Keywords: Leucinol; Leucyl-tRNA synthetase; mTORC1 inhibitor.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Cell Line, Tumor
HEK293 Cells
Humans
Isoleucine-tRNA Ligase / antagonists & inhibitors*
Leucine / analogs & derivatives*
Leucine / chemical synthesis
Leucine / pharmacology
Mechanistic Target of Rapamycin Complex 1
Multiprotein Complexes / antagonists & inhibitors*
Oxazolidinones / chemical synthesis
Oxazolidinones / pharmacology*
Phosphorylation
Ribosomal Protein S6 Kinases / metabolism
Sirolimus / pharmacology
Stereoisomerism
TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

Antineoplastic Agents
Multiprotein Complexes
Oxazolidinones
leucinol
Mechanistic Target of Rapamycin Complex 1
Ribosomal Protein S6 Kinases
TOR Serine-Threonine Kinases
Isoleucine-tRNA Ligase
Leucine
Sirolimus