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

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

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3038-3041
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	13
DOIs	https://doi.org/10.1016/j.bmcl.2016.05.011
Publication status	Published - 2016 Jul 1

Bibliographical note

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© 2016 Elsevier Ltd. All rights reserved.

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2016.05.011

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

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.",

author = "Suyoung Yoon and Kim, {Jong Hyun} and Ina Yoon and Changhoon Kim and Kim, {Sung Eun} and Yura Koh and Jeong, {Seung Jae} and Jiyoun Lee and Sunghoon Kim and Jeewoo Lee",

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AU - Yoon, Suyoung

AU - Kim, Jong Hyun

AU - Yoon, Ina

AU - Kim, Changhoon

AU - Kim, Sung Eun

AU - Koh, Yura

AU - Jeong, Seung Jae

AU - Lee, Jiyoun

AU - Kim, Sunghoon

AU - Lee, Jeewoo

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

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ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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