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

• Published in: Bioorganic & medicinal chemistry 2017-08, Vol.25 (15), p.4145-4152
• Main Authors: Yoon, Suyoung, Kim, Jong Hyun, Koh, Yura, Tran, Phuong-Thao, Ann, Jihyae, Yoon, Ina, Jang, Jayun, Kim, Won Kyung, Lee, Sangkook, Lee, Jiyoun, Kim, Sunghoon, Lee, Jeewoo
• Format: Article
• Language: English
• Subjects: Anticancer agents; Cell Line, Tumor; Drug Discovery; Drug Screening Assays, Antitumor; HEK293 Cells; Humans; Leucine-tRNA Ligase - metabolism; Leucyl-tRNA synthetase; LRS; Mass Spectrometry - methods; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; mTORC1 inhibitor; Phosphorylation; Proton Magnetic Resonance Spectroscopy; Ribosomal Protein S6 Kinases - metabolism; Sulfonic Acids - chemistry; Sulfonic Acids - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.06.002

[Display omitted] 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.