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
  • 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: [email protected].
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.