Recently, non-canonical roles of Lysyl-tRNA Synthetase (KRS), which is associated with cell migration and cancer metastasis, have been reported. Therefore, KRS has emerged as a promising target for the treatment of cell migration-related diseases, especially cancer metastasis, although the satisfying chemical inhibitors targeting KRS have not yet been identified. Here, we report the discovery of novel, mechanistically unique, and potent cell migration inhibitors targeting KRS, including the chemical and biological studies on the most effective N,N-dialkylthiazolo [5,4-b]pyridin-2-amine (SL-1910). SL-1910 exhibited highly potent migration inhibition (EC50 = 81 nM against the mutant KRS-overexpressed MDA-MB-231 cells) and was superior to the previously reported KRS inhibitor (migration inhibitory EC50 = 8.5 μM against H226 cells). The KRS protein binding study via fluorescence-based binding titration and KRS protein 2D-NMR mapping study, in vitro concentration-dependent cell migration inhibition, and in vivo anti-metastatic activity of SL-1910, which consists of a new scaffold, have been reported in this study. In addition, in vitro absorption, distribution, metabolism, and excretion studies and mouse pharmacokinetics experiments for SL-1910 were conducted.
|Journal||European Journal of Medicinal Chemistry|
|Publication status||Published - 2021 Jun 5|
Bibliographical noteFunding Information:
This research was supported by National Research Foundation of Korea grant ( NRF-2020R1A2C1010552 ) and the Global Frontier Project grant ( NRF-M3A6A4-2010-0029785 and NRF-2015M3A6A406572 4) funded by the Ministry of Science and ICT of the Republic of Korea .
© 2021 Elsevier Masson SAS
All Science Journal Classification (ASJC) codes
- Drug Discovery
- Organic Chemistry