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Bioorg Med Chem. 2017 Aug 1;25(15):4145-4152. doi: 10.1016/j.bmc.2017.06.002. Epub 2017 Jun 2.

Discovery of simplified leucyladenylate sulfamates as novel leucyl-tRNA synthetase (LRS)-targeted mammalian target of rapamycin complex 1 (mTORC1) inhibitors.

Author information

1
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
2
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
3
Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi, Viet Nam.
4
Department of Global Medical Science, Sungshin University, Seoul 01133, Republic of Korea.
5
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea.
6
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: jeewoo@snu.ac.kr.

Abstract

Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (1) as LRS-targeted mTORC1 inhibitors. We replaced the adenylate group with a N-(3,4-dimethoxybenzyl)benzenesulfonamide (2a) or a N-(2-phenoxyethyl)benzenesulfonamide groups (2b) that can maintain specific binding, but has more favorable physicochemical properties such as reduced polarity and asymmetric centers. Among these simplified analogues, compound 16 and its constrained analogue 22 effectively inhibited S6K phosphorylation in a dose-dependent manner and exhibited cancer cell specific cytotoxicity against six different types of cancer cells. This result supports that LRS is a viable target for novel anticancer therapy.

KEYWORDS:

Anticancer agents; LRS; Leucyl-tRNA synthetase; mTORC1 inhibitor

PMID:
28625715
DOI:
10.1016/j.bmc.2017.06.002
[Indexed for MEDLINE]

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