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

作者：Yoon Suyoung; Zuo Dongxu; Kim Jong Hyun; Yoon Ina; Ann Jihyae; Kim Sung Eun; Cho Dasol; Kim Won Kyung; Lee Sangkook; Lee Jiyoun^*; Kim Sunghoon; Lee Jeewoo^*

来源：Bioorganic & Medicinal Chemistry, 2018, 26(14): 4073-4079.

DOI：10.1016/j.bmc.2018.06.034

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, LAS-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.

• 出版日期2018-8-7