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

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

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4073-4079
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number14
DOIs
Publication statusPublished - 2018 Aug 7

Bibliographical note

Funding Information:
This research was supported by the Global Frontier Project grant (NRF-2012M3A6A4054928) of National Research Foundation funded by the Ministry of Education , Science and Technology of South Korea.

Funding Information:
This research was supported by the Global Frontier Project grant (NRF-2012M3A6A4054928) of National Research Foundation funded by the Ministry of Education, Science and Technology of South Korea.

Publisher Copyright:
© 2018 Elsevier Ltd

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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