Structure-activity relationship of leucyladenylate sulfamate analogues as leucyl-tRNA synthetase (LRS)-targeting inhibitors of Mammalian target of rapamycin complex 1 (mTORC1)

Suyoung Yoon, Sung Eun Kim, Jong Hyun Kim, Ina Yoon, Phuong Thao Tran, Jihyae Ann, Changhoon Kim, Woong Sub Byun, Sangkook Lee, Sunghoon Kim, Jiyoun Lee, Jeewoo Lee

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Abstract

Leucyl-tRNA synthetase (LRS) plays an important role in amino acid-dependent mTORC1 signaling, which is known to be associated with cellular metabolism and proliferation. Therefore, LRS-targeting small molecules that can suppress mTORC1 activation may provide an alternative strategy to current anticancer therapy. In this work, we developed a library of leucyladenylate sulfate analogues by extensively modifying three different pharmacophoric regions comprising adenine, ribose and leucine. Several effective compounds were identified by cell-based mTORC1 activation assays and further tested for anticancer activity. The selected compounds mostly exhibited selective cytotoxicity toward five different cancer cell lines, supporting the hypothesis that the LRS-mediated mTORC1 pathway is a promising alternative target to current therapeutic approaches.

Original languageEnglish
Pages (from-to)1099-1109
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume27
Issue number6
DOIs
Publication statusPublished - 2019 Mar 15

All Science Journal Classification (ASJC) codes

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

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