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

Yoon, Suyoung; Kim, Jong Hyun; Yoon, Ina; Kim, Chang Hoon; Kim, Sung Eun; Koh, Yura; Jeong, Seung Jae; Lee, Jiyoun; Kim, Sung‐Hoon; Lee, Jeewoo

doi:10.1016/j.bmcl.2016.05.011

Cited by 17 publications

(13 citation statements)

References 22 publications

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“…From a therapeutic point of view, diverse biological activities of human ARSs indicate their potential as therapeutic targets and agents for cancer treatment 1 . For instance, inhibition of the catalytic site 105 and noncatalytic site of LARS1 responsible for interaction with RagD have been shown to be effective in controlling the tumor-promoting mTORC1 pathway 92 . Furthermore, chemical intervention of interaction between KARS1 and 67LR in the cell membrane is effective against cancer metastasis 53 .…”

Section: Discussionmentioning

confidence: 99%

Functional and pathologic association of aminoacyl-tRNA synthetases with cancer

et al. 2022

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Although key tumorigenic and tumor-suppressive factors have been unveiled over the last several decades, cancer remains the most life-threatening disease. Multiomic analyses of patient samples and an in-depth understanding of tumorigenic processes have rapidly revealed unexpected pathologic associations of new cellular factors previously overlooked in cancer biology. In this regard, the newly discovered activities of human aminoacyl-tRNA synthases (ARSs) deserve attention not only for their pathological significance in tumorigenesis but also regarding diagnostic and therapeutic implications. ARSs are not only essential enzymes covalently linking substrate amino acids to cognate tRNAs for protein synthesis but also function as regulators of cellular processes by sensing different cellular conditions. With their catalytic role in protein synthesis and their regulatory role in homeostasis, functional alterations or dysregulation of ARSs might be pathologically associated with tumorigenesis. This review focuses on the potential implications of ARS genes and proteins in different aspects of cancer based on various bioinformatic analyses and experimental data. We also review their diverse activities involving extracellular secretion, protein–protein interactions, and amino acid sensing, which are related to cancers. The newly discovered cancer-related activities of ARSs are expected to provide new opportunities for detecting, preventing and curing cancers.

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Section: Discussionmentioning

confidence: 99%

Functional and pathologic association of aminoacyl-tRNA synthetases with cancer

et al. 2022

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“…These five-membered heterocyclic compounds are P2X7, 3 neurokinin 1 (NK 1 ), 4 and muscarinic acetylcholine 5 receptor antagonists. Some of them inhibit various ferments, such as leucyl-tRNA synthetase, 6 -secretase, 7 HIV-1 protease, 8,9 and biotin biosynthesis, 10 and exhibit antimicrobial and antihepatitis С activity 11 (Figure 1). The six-membered cyclic urea moiety is also found in a number of drugs, such as well-known barbiturates, the anti-HIV drug lopinavir, 12 the antibiotic sparsomycin, 13 and the actively studied anticancer agent troxacitabine.…”

Section: Published As Part Of the Special Topic Recent Advances In Ammentioning

confidence: 99%

Nucleophilic Cyclization/Electrophilic Substitution of (2,2-Dialkoxyethyl)ureas: Highly Regioselective Access to Novel 4-(Het)arylimidazolidinones and Benzo[d][1,3]diazepinones

et al. 2020

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Imidazolidin-2-one and 1,3-benzodiazepin-2-one scaffolds are structural motifs of many biologically active compounds. Herein, we report a highly regioselective acid-catalyzed intramolecular nucleophilic cyclization/intermolecular electrophilic substitution reaction sequence of (2,2-dialkoxyethyl)ureas. The reaction benefits from readily available starting materials, a simple workup procedure, moderate to high yields of target compounds, and provides a convenient entry to previously unknown 4-(het)arylimidazolidinones and 5-(het)arylbenzodiazepinones. The proposed mechanism of the reaction is also discussed.

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“…Similarly, the LARS1 inhibitor BC-LI-0186 at nanomolar concentration exhibits potent anti-tumor activity against lung cancer cells [203] . Recent studies highlight the role of LARS1 in mTORC1 activation and competitive inhibitors of LARS1, e.g., leucinol and leucyladenylate sulfate derivatives, prevent leucine-mediated activation of mTORC1 [204] , [205] , [206] , [207] , [208] , [209] . Similarly, BC-LI-0186 prevents LARS1 lysosomal localization and mTORC1 activation by blocking RagD-LARS1 interaction [51] .…”

Section: Aarss and Immune Regulation: A Potential Link To Cancer Deve...mentioning

confidence: 99%

Aminoacyl-tRNA synthetases of the multi-tRNA synthetase complex and their role in tumorigenesis

Khan

Fox

2022

Translational Oncology

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

Cited by 17 publications

References 22 publications

Functional and pathologic association of aminoacyl-tRNA synthetases with cancer

Functional and pathologic association of aminoacyl-tRNA synthetases with cancer

Nucleophilic Cyclization/Electrophilic Substitution of (2,2-Dialkoxyethyl)ureas: Highly Regioselective Access to Novel 4-(Het)arylimidazolidinones and Benzo[d][1,3]diazepinones

Aminoacyl-tRNA synthetases of the multi-tRNA synthetase complex and their role in tumorigenesis

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