生物活性
Momelotinib (CYT387)是一种ATP竞争性JAK1/JAK2抑制剂，IC50为11 nM/18 nM，比作用于JAK3选择性约高10倍左右。CYT387有效且选择性作用于JAK1和JAK2，IC50分别为11 nM和 18 nM, 效果比作用于密切相关的JAK3激酶(IC50为155 nM)高9倍。在体外, CYT387抑制IL-3 刺激的 亲本Ba/F3细胞(Ba/F3-wt) 增殖，IC50为1400 nM。而且, CYT387 作用于组成型激活的 JAK2 或 MPL信号 的细胞系,包括 Ba/F3-MPLW515L细胞, CHRF-288-11 细胞，和Ba/F3-TEL-JAK2细胞，也抑制细胞增殖，IC50分别为200 nM, 1 nM 和 700 nM。
化学数据
| 分子量 | 414.46 |
| 分子式 | C23H22N6O2 |
| CAS号 | 1056634-68-4 |
| 纯度 | 98.82% |
| 溶解性（25°C） | DMSO 63 mg/mL |
| 储存和运输条件 | 固体粉末： -20°C 冷藏长期储存
常温运输及临时存放 |
实验操作 来自于公开的文献，仅供相同实验参考（如实验材料、目的不同，请参考其他文献）
| 细胞实验 |
|---|
| 细胞系 | Ba/F3 cells expressing JAK2V617F (Ba/F3-JAK2V617F) and MPLW515L (Ba/F3–MPLW515L) mutants, as well as CHRF-288-11 (JAK2T875N) and CMK (JAK3A572V) cells |
| 方法 | Cell-based assays. Ba/F3 cells expressing JAK2V617F (Ba/F3-JAK2V617F) and MPLW515L (Ba/F3–MPLW515L) mutants, as well as CHRF-288-11 (JAK2T875N) and CMK (JAK3A572V) cells were generously provided by D Gary Gilliland (Brigham and Women’s Hospital, Boston, MA, USA). The TEL/JAK2 and TEL/ JAK3 fusions were generated and introduced into Ba/F3 murine cells as described earlier. The TEL/JAK2- or TEL/JAK3-transfected cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) containing 10% fetal calf serum (FCS). Ba/F3 wild-type cells were cultured in RPMI containing 10% FCS supplemented with 5 ng/ml murine IL-3 (Peprotech, Rocky Hill, NJ, USA). Proliferation was measured using the Alamar Blue assay (TREK Diagnostic Systems, Cleveland, OH, USA) after incubating for 72 h at 37℃with 5% CO2. |
| 浓度 | 0~100μM |
| 处理时间 | 72 h |
| 动物实验 |
|---|
| 动物模型 | murine model of JAK2V617F-dependent MPN |
| 配制 | dissolved in NMP (120 mg/mL final; 1-methyl-2-pyrrolidinone, Chromasolv Plus; Sigma-Aldrich). Subsequently, the CYT387/NMP mix was diluted with 0.14M Captisol (Cydex Pharmaceuticals Inc) to a concentration of 6 mg/mL and further diluted with 0.1M Captisol to a final concentration of 4 mg/mL. |
| 剂量 | 25, 50mg/kg twice daily from day 34 to day 82 |
| 给药处理 | oral gavage |
不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）
| 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。
储备液配制
以下数据基于产品分子量，对于特殊产品，请参照COA中的储备液配制条件和说明进行操作。
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 2.4128 mL | 12.0639 mL | 24.1278 mL |
| 5 mM | 0.4826 mL | 2.4128 mL | 4.8256 mL |
| 10 mM | 0.2413 mL | 1.2064 mL | 2.4128 mL |
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