Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Bioorg Med Chem. 2019 Mar 15;27(6):1099-1109. doi: 10.1016/j.bmc.2019.01.037. Epub 2019 Jan 30.
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.
亮氨酰-tRNA 合成酶 (LRS) 在氨基酸依赖性 mTORC1 信号转导中发挥重要作用，已知其与细胞代谢和增殖有关。因此，靶向 LRS 以抑制 mTORC1 激活的小分子可能为当前的抗癌治疗提供替代策略。在这项工作中，我们通过广泛修饰包含腺嘌呤、核糖和亮氨酸的三个不同药效团区域，开发了亮氨酰腺苷酸硫酸盐类似物库。通过基于细胞的 mTORC1 激活测定鉴定了几种有效的化合物，并进一步测试了它们的抗癌活性。所选化合物对五种不同的癌细胞系大多表现出选择性细胞毒性，支持 LRS 介导的 mTORC1 途径是当前治疗方法的有前途的替代靶标的假说。
