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.
Bibliographical noteFunding 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 Korea and the Basic Science Research Program (NRF-2018R1D1A1B07042846) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT of Korea.
© 2019 Elsevier Ltd
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry