| Description | BC-LI-0186 (4-(2,3-dimethyl-5-oxo-4-propan-2-ylpyrazol-1-yl)-N-(2-phenoxyethyl)benzenesulfonamide) is a potent and selective inhibitor of the interaction of Leucyl-tRNA synthetase (LRS) and Ras-related GTP-binding protein D (RagD) with IC50 of 46.11 nM. BC-LI-0186 competitively binds the RagD interaction site of LRS with Kd of 42.1 nM and has no effect on LRS-vps34, LRS-eprs, RagB-RagD association, mTORC1 complex formation. BC-LI-0186 potently inhibits the activity of tumor-associated MTOR mutants and the growth of rapamycin-resistant cancer cells. BC-LI-0186 can be used for lung cancer-related research. |
| In vitro | 0-20μM BC-LI-0186的给药，接着在无亮氨酸培养基中饥饿90分钟，然后在无血清培养基中饥饿15分钟，可以剂量和时间依赖性地抑制S6K的磷酸化，但对AKT（S473）的磷酸化无影响[1]。给予0-20μM BC-LI-0186作用6小时，可诱导A549和H460细胞中剪切的poly ADP-核糖聚合酶（PARP）和caspase-3的活化，以及p62的增加[1]。在NSCLC细胞中，BC-LI-0186展现出纳摩尔浓度的细胞毒性效应，其IC50值在A549、H460、H2228、H1703、SNU1330、H1650、H2009、H358、H2279、H460及H596细胞中分别为98 nM、206 nM、55 nM、78 nM、83 nM、86 nM、102 nM、109 nM、128 nM和206 nM[1]。BC-LI-0186能克服获得的雷帕霉素（rapamycin）耐药性，并在具有M TOR WT（HCT116 MW）或S2035I突变（HCT116 MM）的等基因HCT116细胞线中抑制mTORC1途径，其在野生型和突变细胞间的效能变化不大（GI50: 39.49 nM和42.03 nM，EC50: 105.03 nM和100.45 nM）[1]。 |
| In vivo | 经腹腔注射50mg/kg BC-LI-0186单独使用或与cisplatin结合使用，连续2周（每周5天，每天两次）在LSL K-ras G12D肺癌动物模型中展示出抗肿瘤效果，并与相比较仅用载体处理的情况，显著减小了肿瘤体积[1]。 |
| Target activity | LeuRS-RagD:42.1 nM(Kd), LeuRS-RagD:46.11 nM |
| Synonyms | 4-(2,3-dimethyl-5-oxo-4-propan-2-ylpyrazol-1-yl)-N-(2-phenoxyethyl)benzenesulfonamide |
| molecular weight | 429.53 |
| Molecular formula | C22H27N3O4S |
| CAS | 695207-56-8 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| Solubility | DMSO: 100 mg/mL (232.81 mM) |
| References | 1. Jong Hyun Kim, 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, Kwon J, Kim JH, Jung M, Kim SK, Kim S, Mun JY. Leucine-induced localization of Leucyl-tRNA synthetase in lysosome membrane. Biochem Biophys Res Commun. 2017 Nov 18;493(2):1129-1135. 3. Lee M, Kim JH, Yoon I, Lee C, Fallahi Sichani M, Kang JS, Kang J, Guo M, Lee KY, Han G, Kim S, Han JM. Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway. Proc Natl Acad Sci U S A. 2018 Jun 5;115(23):E5279-E5288. |