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

Yoon, Suyoung; Zuo, Dongxu; Kim, Jong Hyun; Yoon, Ina; Ann, Jihyae; Kim, Sung Eun; Cho, Dasol; Kim, Won Kyung; Lee, Sang-Kook; Lee, Jiyoun; Kim, Sung‐Hoon; Lee, Jeewoo

doi:10.1016/j.bmc.2018.06.034

Cited by 11 publications

(5 citation statements)

References 19 publications

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“…LARS expression was reported to be upregulated in several cancers including lung cancer [6,8]. Thus, many investigators have tried to develop novel anticancer agents targeting LARS [7][8][9][10][11][12][13]. However, the biological and clinical significance of LARS expression in CRC has not been reported yet.…”

Section: Discussionmentioning

confidence: 99%

“…LARS was reported to be closely related to the growth and migration of lung cancer cells by observing the reduced migration and colony formation from LARS1 siRNA knockdown in a lung cancer cell line [6]. LARS expression has no reported biological or clinical implications in CRC patients, even though a few compounds targeting LARS as potential anticancer agents have been developed and their action mechanisms are studied [7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Dickkopf 4 Alone and in Combination with Leucyl-tRNA Synthetase as a Good Prognostic Biomarker for Human Colorectal Cancer

Park

Cho

Han

et al. 2023

BioMed Research International

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The prognosis of patients with colorectal cancer (CRC) is affected by invasion and metastasis. Leucyl-tRNA synthetase (LARS) was shown to be related to the growth and migration of lung cancer cells. Dickkopf 4 (DKK4) is known as a Wnt/β-catenin pathway inhibitor, and its upregulation was reported in several cancers. However, the clinical significance of LARS and DKK4 in human CRC has not been clearly defined. We investigated the expression of LARS and DKK4 by immunohistochemical staining in tissue microarrays from 642 primary CRC patients and analyzed the relationship between their expression and the clinicopathological characteristics of CRC patients. LARS and DKK4 expressions were not related to gender, age at surgery, histologic grade, size, tumor location, tumor invasion, or metastasis, but LARS expression was significantly correlated with TNM stage, N stage, and lymph node metastasis. DKK4 expression was inversely related to the TNM stage and N stage. Survival analysis demonstrated that the OS and DFS in the LARS high expression group were not different compared to the LARS low expression group. OS and DFS in the DKK4 high expression group were significantly higher than in the DKK4 low expression group. In addition, OS and DFS in the group with the combination of the LARS high/DKK4 low expression were significantly lower than in the LARS high/DKK4 high expression group. The low expression of DKK4 alone can be used as a predictor of relapse in CRC patients. In addition, DKK4 low expression in the case of LARS high expression can be used as a poor prognostic factor in CRC patients. Thus, our findings suggest that DKK4 alone or in combination with LARS at diagnosis may be a useful prognostic factor for CRC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dickkopf 4 Alone and in Combination with Leucyl-tRNA Synthetase as a Good Prognostic Biomarker for Human Colorectal Cancer

Park

Cho

Han

et al. 2023

BioMed Research International

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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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“…Intriguingly, Lee and colleagues [125–127] have recently developed analogues of leucyl-AMS (not shown) as potential anticancer agents. However, rather than inhibiting the catalytic activity of leucyl-tRNA synthetase, these analogues selectively block a second, non-catalytic function, in which the protein acts as a leucinesensing GTPase activating protein for Rag GTPase, leading to activation of the mTORC1 complex that regulates protein translation and cell growth [128, 129].…”

Section: Rational Design Of Acyl-ams Inhibitors Of Adenylate-forming mentioning

confidence: 99%

Targeting adenylate-forming enzymes with designed sulfonyladenosine inhibitors

2019

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Adenylate-forming enzymes are a mechanistic superfamily that are involved in diverse biochemical pathways. They catalyze ATP-dependent activation of carboxylic acid substrates as reactive acyl adenylate (acyl-AMP) intermediates and subsequent coupling to various nucleophiles to generate ester, thioester, and amide products. Inspired by natural products, acyl sulfonyladenosines (acyl-AMS) that mimic the tightly bound acyl-AMP reaction intermediates have been developed as potent inhibitors of adenylate-forming enzymes. This simple yet powerful inhibitor design platform has provided a wide range of biological probes as well as several therapeutic lead compounds. Herein, we provide an overview of the nine structural classes of adenylate-forming enzymes and examples of acyl-AMS inhibitors that have been developed for each.

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

Cited by 11 publications

References 19 publications

Dickkopf 4 Alone and in Combination with Leucyl-tRNA Synthetase as a Good Prognostic Biomarker for Human Colorectal Cancer

Dickkopf 4 Alone and in Combination with Leucyl-tRNA Synthetase as a Good Prognostic Biomarker for Human Colorectal Cancer

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

Targeting adenylate-forming enzymes with designed sulfonyladenosine inhibitors

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