Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS)-Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors,Journal of Medicinal Chemistry

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Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS)-Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-11-09 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01190
Suyoung Yoon ₁ , Jong Hyun Kim ₂ , Sung-Eun Kim ₁ , Changhoon Kim ₁ , Phuong-Thao Tran ₁ , Jihyae Ann ₁ , Yura Koh ₁ , Jayun Jang ₂ , Sungmin Kim ₂ , Hee-sun Moon ₂ , Won Kyung Kim ₁ , Sangkook Lee ₁ , Jiyoun Lee ₃ , Sunghoon Kim _{2,

4} , Jeewoo Lee ₁

Affiliation

Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound 18 selectively inhibited LRS-mediated mTORC1 activation and exerted specific cytotoxicity against colon cancer cells with a hyperactive mTORC1, suggesting that 18 may offer a novel treatment option for human colorectal cancer.

中文翻译：

作为新的亮氨酰tRNA合成酶（LRS）靶向的雷帕霉素复合物1（mTORC1）抑制剂的哺乳动物目标亮氨酸腺苷磺酸盐的发现。

最近的研究表明，LRS可能充当mTORC1途径的亮氨酸传感器，可能为克服癌症治疗中雷帕霉素耐药性提供了另一种策略。在这项研究中，我们开发了亮环戊二酸氨基磺酸酯衍生物作为靶向LRS的mTORC1抑制剂。化合物18选择性抑制LRS介导的mTORC1活化，并对具有高活性mTORC1的结肠癌细胞产生特定的细胞毒性，这表明18可能为人类结直肠癌提供新的治疗选择。

更新日期：2016-11-09

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