Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 03722, Republic of Korea; Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
Department of pharmacy, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.
Bioorg Chem. 2021 Jul;112:104907. doi: 10.1016/j.bioorg.2021.104907. Epub 2021 Apr 20.
The enzyme leucyl-tRNA synthetase (LRS) and the amino acid leucine regulate the mechanistic target of rapamycin (mTOR) signaling pathway. Leucine-dependent mTORC1 activation depends on GTPase activating protein events mediated by LRS. In a prior study, compound BC-LI-0186 was discovered and shown to interfere with the mTORC1 signaling pathway by inhibiting the LRS-RagD interaction. However, BC-LI-0186 exhibited poor solubility and was metabolized by human liver microsomes. In this study, in silico physicochemical properties and metabolite analysis of BC-LI-0186 are used to investigate the addition of functional groups to improve solubility and microsomal stability. In vitro experiments demonstrated that 7b and 8a had improved chemical properties while still maintaining inhibitory activity against mTORC1. The results suggest a new strategy for the discovery of novel drug candidates and the treatment of diverse mTORC1-related diseases.
亮氨酰-tRNA 合成酶（LRS）和亮氨酸这两种酶和氨基酸可以调节雷帕霉素靶蛋白（mTOR）信号通路。亮氨酸依赖的 mTORC1 激活依赖于 LRS 介导的 GTPase 激活蛋白事件。在之前的研究中，发现了化合物 BC-LI-0186，它通过抑制 LRS-RagD 相互作用来干扰 mTORC1 信号通路。然而，BC-LI-0186 的溶解度较差，并且会被人肝微粒体代谢。在本研究中，通过计算物理化学性质和代谢物分析来研究添加功能基团以提高溶解度和微粒体稳定性。体外实验表明，7b 和 8a 具有改善的化学性质，同时仍然保持对 mTORC1 的抑制活性。这些结果为发现新型药物候选物和治疗各种 mTORC1 相关疾病提供了新的策略。
