BC-LI-0186 is a potent and highly selective inhibitor of the interaction between leucyl-tRNA synthetase (LRS) and Ras-related GTP-binding protein D (RagD), with an IC₅₀ value of 46.11nM[1-2]. By competitively binding to the RagD interaction site on the LRS protein, BC-LI-0186 specifically disrupts the LRS – RagD interaction and induces apoptosis in cancer cells. BC-LI-0186 is primarily used in cancer‑related research[3-4].
In vitro, treatment of SW620 colon cancer cells with BC-LI-0186 (0.1–20μM) for 24 hours. BC-LI-0186 significantly inhibited leucine‑induced S6K phosphorylation and blocked the interaction between LRS and RagD, thereby suppressing mTORC1 signaling activation and ultimately inducing cancer cell apoptosis[1]. In C2C12 myoblasts, treatment with BC-LI-0186 (4μM) for 72 hours. BC-LI-0186 disrupted LRS – RagD binding, relieved mTORC1‑mediated suppression of the IRS1‑PI3K‑Akt pathway, and significantly promoted myogenic differentiation[5].
In vivo, in an LSL K‑ras G12D mouse lung cancer model, BC-LI-0186 (20mg/kg; intraperitoneal injection; 5 days per week for 2 weeks) significantly reduced tumor volume, increased expression of activated caspase‑3 in tumor tissue, and inhibited phosphorylation of the mTORC1 signaling markers pS6 and pAKT[6]. In a BALB/c nude mouse H460 cell xenograft model, BC-LI-0186 (20mg/kg; i.p.; 5 days per week for 2 weeks) combined with trametinib (1mg/kg; oral; 5 days per week) synergistically suppressed tumor growth, decreased the tumor volume increase rate, enhanced activated caspase‑3 expression in tumor tissue, and inhibited pMEK and pS6 signaling pathway activation without causing significant body weight changes[7].
References:
[1] Kim JH, Lee C, Lee M, et al. Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction. Nat Commun. 2017 Sep 29;8(1):732.
[2] Choi H, Son JB, Kang J, et al. Leucine-induced localization of Leucyl-tRNA synthetase in lysosome membrane. Biochem Biophys Res Commun. 2017 Nov 18;493(2):1129-1135.
[3] Kim JH, Jung K, Lee C, et al. Structure-based modification of pyrazolone derivatives to inhibit mTORC1 by targeting the leucyl-tRNA synthetase-RagD interaction. Bioorg Chem. 2021 Jul;112:104907.
[4] You JS, Karaman K, Reyes-Ordoñez A, et al. Leucyl-tRNA Synthetase Contributes to Muscle Weakness through Mammalian Target of Rapamycin Complex 1 Activation and Autophagy Suppression in a Mouse Model of Duchenne Muscular Dystrophy. Am J Pathol. 2024 Aug;194(8):1571-1580.
[5] Son K, You JS, Yoon MS, et al. Nontranslational function of leucyl-tRNA synthetase regulates myogenic differentiation and skeletal muscle regeneration. J Clin Invest. 2019 Apr 15;129(5):2088-2093.
[6] Kim EY, Lee JG, Lee JM, et al. Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer. Ther Adv Med Oncol. 2019 May 19;11:1758835919846798.
[7] Lee SH, Kim EY, Han JM, et al. Combination of the LARS1 Inhibitor, BC-LI-0186 with a MEK1/2 Inhibitor Enhances the Anti-Tumor Effect in Non-Small Cell Lung Cancer. Cancer Res Treat. 2023 Jul;55(3):851-864.
BC-LI-0186是一种有效、高选择性的亮氨酰-tRNA合成酶（LRS）与Ras相关GTP结合蛋白D（RagD）相互作用的抑制剂，IC50值为46.11nM[1-2]。BC-LI-0186通过竞争性地与LRS蛋白上与RagD相互作用的位点结合，从而特异性破坏LRS-RagD的相互作用，引起癌细胞凋亡。BC-LI-0186主要用于癌症相关的研究[3-4]。
在体外，BC-LI-0186（0.1-20μM）处理SW620结肠癌细胞24小时，BC-LI-0186可显著抑制亮氨酸诱导的S6K磷酸化，并阻断LRS与RagD的相互作用，从而抑制mTORC1信号通路激活，最终诱导癌细胞凋亡[1]。BC-LI-0186（4μM）处理C2C12成肌细胞72h，BC-LI-0186通过破坏LRS-RagD结合，解除mTORC1对IRS1-PI3K-Akt通路的抑制，显著促进成肌分化[5]。
在体内，在LSL K-ras G12D小鼠肺癌模型中，BC-LI-0186（20mg/kg；腹腔注射；每周5天持续2周）显著降低肿瘤体积，并诱导肿瘤组织中活化caspase-3表达增加，同时抑制mTORC1信号标志pS6和pAKT的磷酸化水平[6]。在BALB/c裸鼠H460细胞异种移植模型中，BC-LI-0186（20mg/kg；腹腔注射；每周5天持续2周）联合曲美替尼（1mg/kg；口服；每周5天）显著协同抑制肿瘤生长，降低肿瘤体积增加率，并增强肿瘤组织中活化caspase-3表达，同时抑制pMEK和pS6信号通路激活，且未引起显著体重变化[7]。