Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 25, Issue 15, Pages 4145-4152Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.06.002
Keywords
Leucyl-tRNA synthetase; LRS; mTORC1 inhibitor; Anticancer agents
Funding
- Global Frontier Project grant of National Research Foundation - Ministry of Education, Science and Technology of Korea [NRF-2012M3A6A4054928]
- National Research Foundation of Korea [2012M3A6A4054928] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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. (C) 2017 Elsevier Ltd. All rights reserved.
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