MLi-2 是一种高选择性的，具有口服活性的 LRRK2 抑制剂，在纯化的LRRK2激酶体外测定中的IC50值为0.76 nM，在pSer935 LRRK2去磷酸化的细胞测定中的IC50值为1.4 nM，在放射性配体竞争结合测定中的IC50值为3.4 nM。
别名：MLi2
MLi-2 is a highly potent, and selective LRRK2 kinase inhibitor with central nervous system activity. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro (IC50 = 0.76 nM), a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 (IC50 = 1.4 nM), and a radioligand competition binding assay (IC50 = 3.4 nM). MLi-2 has greater than 295-fold selectivity for over 300 kinases in addition to a diverse panel of receptors and ion channels.
Acute oral and subchronic dosing in MLi-2 mice resulted in dosedependent central and peripheral target inhibition over a 24-hour period as measured by dephosphorylation of pSer935 LRRK2. Treatment of MitoPark mice with MLi-2 is well tolerated over a 15-week period at brain and plasma exposures >100× the in vivo plasma IC50 for LRRK2 kinase inhibition as measured by pSer935 dephosphorylation. Morphologic changes in the lung, consistent with enlarged type II pneumocytes, are observed in MLi-2-treated MitoPark mice.
| 体外实验* | |
|---|---|
| 细胞系 | SH-SY5Y cells |
| 方法 | A human neuroblastoma cell line, SH-SY5Y, is used for the LRRK2 stable cell line construction. SH-SY5Y cells are cultured in Dulbecco’s modified Eagle’s medium/F-12 supplemented with GlutaMax, 10% tetracycline (Tet)-free fetal bovine serum, nonessential amino acids, pen-strep at 37°C and 5% carbon dioxide. Parental cells are transfected with plasmid constructs that overexpress full-length human LRRK2 wildtype or mutant (G2019S) under the control of a Tet-inducible promoter. Transfected cells are selected and maintained with hygromycin (2 mg/ml) and zeocin (100 mg/ml). Cells are seeded into six-well plates and induced with Tet (2 mg/ml) for 72 hours prior to treatment. After 90 minutes of MLi-2 incubation, cells were mechanically lifted, pelleted, and lysed with lysis buffer supplemented with protease, and phosphatase inhibitors. Pellets are further bead homogenized and then spun at 13,200 rpm for 20 minutes at 4°C. Supernatants are then removed for subsequent Western blot analyses. |
| 浓度 | 10 serial 3-fold dilutions, top concentration 5 μM |
| 处理时间 | 90 min |
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
| 体内实验* | |
|---|---|
| 动物模型 | male C57Bl/6 mice weighing 20-25g |
| 配制 | suspended in 30% Captisol |
| 剂量 | 1-100 mg/kg; administered in a volume of 10 ml/kg |
| 给药处理 | IV or PO administration |
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
| 分子量 | 379.46 |
| 分子式 | C21H25N5O2 |
| CAS号 | 1627091-47-7 |
| 溶解性（25°C） | DMSO 60 mg/mL |
| 储存条件 |
粉末型式 -20°C 3年；4°C 2年 溶于溶剂 -80°C 6个月；-20°C 1个月 |
| 运输方式 | 冰袋运输，根据产品的不同，可能会有相应调整。 |
*下述溶液配置方法仅为基于分子量计算出的理论值。不同产品在配置溶液前，需考虑其在不同溶剂中的溶解度限制。
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 2.6353 mL | 13.1766 mL | 26.3532 mL |
| 5 mM | 0.5271 mL | 2.6353 mL | 5.2706 mL |
| 10 mM | 0.2635 mL | 1.3177 mL | 2.6353 mL |
| 小鼠 | 大鼠 | 兔 | 豚鼠 | 仓鼠 | 狗 | |
| 重量 (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| 体表面积 (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km 系数 | 3 | 6 | 12 | 8 | 5 | 20 |
| 动物 A (mg/kg) = 动物 B (mg/kg) × | 动物 B的Km系数 |
| 动物 A的Km系数 |
例如，依据体表面积折算法，将化合物用于小鼠的剂量20 mg/kg 换算成大鼠的剂量，需要将20 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到化合物用于大鼠的等效剂量为10 mg/kg。
| 其他相关的LRRK2产品 |
|---|
| LRRK2-IN-8
LRRK2-IN-8 是一种 LRRK2 抑制剂。 |
| LRRK2/NUAK1/TYK2-IN-1
LRRK2/NUAK1/TYK2-IN-1 显示出对 LRRK2 (Wt)、LRRK2 (G2019)、TYK2 和 NUAK1 的抑制活性，其 IC50 值小于 10 nM。 |
| EB-42486
EB-42486 是一种新型有效、高选择性的 G2019S-LRRK2 抑制剂（IC50 < 0.2 nM）。 |
| CZC-54252
CZC-54252 is a potent and selective LRRK2 inhibitor with IC50s of 1.28 nM and 1.85 nM for human wild type LRRK2 and G2019S LRRK2, respectively. |
| WAY-333491
WAY-333491 is a LRRK2 kinase inhibitor. |
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