Structure-activity relationship of leucyladenylate sulfamate analogues as leucyl-tRNA synthetase (LRS)-targeting inhibitors of Mammalian target of rapamycin complex 1 (mTORC1) |
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Authors: | Suyoung Yoon Sung-Eun Kim Jong Hyun Kim Ina Yoon Phuong-Thao Tran Jihyae Ann Changhoon Kim Woong Sub Byun Sangkook Lee Sunghoon Kim Jiyoun Lee Jeewoo Lee |
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Affiliation: | 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 Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea;4. Department of Medicinal Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi, Viet Nam;5. Department of Global Medical Science, Sungshin University, Seoul 01133, Republic of Korea |
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Abstract: | Leucyl-tRNA synthetase (LRS) plays an important role in amino acid-dependent mTORC1 signaling, which is known to be associated with cellular metabolism and proliferation. Therefore, LRS-targeting small molecules that can suppress mTORC1 activation may provide an alternative strategy to current anticancer therapy. In this work, we developed a library of leucyladenylate sulfate analogues by extensively modifying three different pharmacophoric regions comprising adenine, ribose and leucine. Several effective compounds were identified by cell-based mTORC1 activation assays and further tested for anticancer activity. The selected compounds mostly exhibited selective cytotoxicity toward five different cancer cell lines, supporting the hypothesis that the LRS-mediated mTORC1 pathway is a promising alternative target to current therapeutic approaches. |
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Keywords: | Leucyl-tRNA synthetase LRS mTORC1 inhibitor Leucyladenylate Anticancer agents |
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