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.