College of Pharmacy, CHA University, Gyeonggi-do, 11160, Republic of Korea; College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy and College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon, South Korea, 21983.
Eur J Med Chem. 2021 Jun 5;218:113405. doi: 10.1016/j.ejmech.2021.113405. Epub 2021 Mar 30.
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 (EC = 81 nM against the mutant KRS-overexpressed MDA-MB-231 cells) and was superior to the previously reported KRS inhibitor (migration inhibitory EC = 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.
最近，与细胞迁移和癌症转移相关的赖氨酸 tRNA 合成酶（KRS）的非典型作用已被报道。因此，KRS 已成为治疗与细胞迁移相关疾病（尤其是癌症转移）的有前途的靶标，尽管尚未发现针对 KRS 的令人满意的化学抑制剂。在这里，我们报告了针对 KRS 的新型、机制独特且强效的细胞迁移抑制剂的发现，包括对最有效的 N，N-二烷基噻唑并[5,4-b]吡啶-2-胺（SL-1910）的化学和生物学研究。SL-1910 表现出高度有效的迁移抑制作用（对突变型 KRS 过表达 MDA-MB-231 细胞的 EC = 81 nM），优于先前报道的 KRS 抑制剂（对 H226 细胞的迁移抑制 EC = 8.5 μM）。本研究报道了通过荧光结合滴定和 KRS 蛋白 2D-NMR 图谱研究进行的 KRS 蛋白结合研究、体外浓度依赖性细胞迁移抑制以及 SL-1910 的体内抗转移活性，SL-1910 由一个新骨架组成。此外，还进行了 SL-1910 的体外吸收、分布、代谢和排泄研究以及小鼠药代动力学实验。
