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Discovery of novel leucyladenylate sulfamate surrogates as leucyl-tRNA synthetase (LRS)-targeted mammalian target of rapamycin complex 1 (mTORC1) inhibitors
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2018-06-26 , DOI: 10.1016/j.bmc.2018.06.034
Suyoung Yoon , Dongxu Zuo , Jong Hyun Kim , Ina Yoon , Jihyae Ann , Sung-Eun Kim , Dasol Cho , Won Kyung Kim , Sangkook Lee , Jiyoun Lee , Sunghoon Kim , Jeewoo Lee

According to recent studies, leucyl-tRNA synthetase (LRS) acts as a leucine sensor and modulates the activation of the mammalian target of rapamycin complex 1 (mTORC1) activation. Because overactive mTORC1 is associated with several diseases, including colon cancer, LRS-targeted mTORC1 inhibitors represent a potential option for anti-cancer therapy. In this work, we developed a series of simplified leucyladenylate sulfamate analogues that contain the N-(3-chloro-4-fluorophenyl)quinazolin-4-amine moiety to replace the adenine group. We identified several compounds with comparable activity to previously reported inhibitors and exhibited selective mTORC1 inhibition and anti-cancer activity. This study further supports the hypothesis that LRS is a promising target to modulate the mTORC1 pathway.



中文翻译:

发现新型亮氨酰磺酸氨基磺酸替代物作为雷帕霉素复合物1(mTORC1)抑制剂的亮氨酰-tRNA合成酶(LRS)靶向的哺乳动物靶标

根据最近的研究,亮氨酰-tRNA合成酶(LRS)充当亮氨酸传感器,并调节哺乳动物雷帕霉素复合物1(mTORC1)靶标的激活。由于过度活跃的mTORC1与包括结肠癌在内的多种疾病有关,因此靶向LRS的mTORC1抑制剂代表了抗癌治疗的潜在选择。在这项工作中,我们开发了一系列简化的亮氨苄基磺酸盐类似物,其中包含N-(3-氯-4-氟苯基)喹唑啉-4-胺部分来取代腺嘌呤基团。我们鉴定了几种与先前报道的抑制剂具有可比活性的化合物,并表现出选择性的mTORC1抑制和抗癌活性。这项研究进一步支持以下假设:LRS是调节mTORC1途径的有希望的靶标。

更新日期:2018-06-26
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