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

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

  • Bioorg Med Chem. 2018 Aug 7;26(14):4073-4079. doi: 10.1016/j.bmc.2018.06.034.
Suyoung Yoon 1,  Dongxu Zuo 1,  Jong Hyun Kim 2,  Ina Yoon 2,  Jihyae Ann 1,  Sung-Eun Kim 1,  Dasol Cho 1,  Won Kyung Kim 1,  Sangkook Lee 1,  Jiyoun Lee 3,  Sunghoon Kim 4,  Jeewoo Lee 5
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 3 Department of Global Medical Science, Sungshin University, Seoul 01133, Republic of Korea.
  • 4 Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea.
  • 5 Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: jeewoo@snu.ac.kr.
PMID: 30041947 DOI: 10.1016/j.bmc.2018.06.034
Abstract

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.

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