Pexmetinib（ARRY-614）是细胞因子合成的有效抑制剂，通过对 p38促分裂原活化蛋白激酶和Tie2/Tek受体酪氨酸激酶的双重抑制（MAPK）来发挥作用。ARRY-614体外抑制Tie2和p38促分裂原活化蛋白激酶的IC50值分别是1000 ng/mL和100 ng/mL[1,2]。

p38是一组促分裂原活化蛋白激酶。MAPKs通过在亚结构域VIII的Thr-Xaa-Tyr基序中酪氨酸和苏氨酸位点的双重磷酸化而激活。数据表明，p38蛋白可能介导细胞核信号[3]。

ARRY-614针对细胞中MAPK和Tie2/Tek受体酪氨酸激酶发挥功能。在原代人骨髓基质细胞中，ARRY-614抑制基础的细胞因子，IC50值范围为50-100 nM [4]。

在剂量递增或扩张实验中，45个病人每日一次或两次接受ARRY-614治疗。ARRY-614减少骨髓中循环生物标志物的水平和p38蛋白的活化[1]。在离体刺激的人全血中，ARRY-614抑制LPS诱导的细胞因子，IC50值范围为50-120 nM。ARRY-614抑制接种SEA或LPS的小鼠释放IL-6，ED50值小于10 mg/kg。 ARRY-614与lenalidomide共同作用时，会抑制体内的促炎细胞因子和肿瘤生长，与单独的任一药剂相比，具有更高的效力[4]。

参考文献：
[1].  Garcia-Manero G, Khoury HJ, Jabbour E, et al. A phase I study of oral ARRY-614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes. Clinical Cancer Research, 2015, 21(5): 985-994.
[2].  Wollenberg LA, Corson DT, Nugent CA, et al. An exploratory, randomized, parallel-group, open-label, relative bioavailability study with an additional two-period crossover food-effect study exploring the pharmacokinetics of two novel formulations of pexmetinib (ARRY-614). Clinical pharmacology: advances and applications, 2015, 7: 87.
[3].  Raingeaud J, Whitmarsh AJ, Barrett T, et al. MKK3-and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Molecular and cellular biology, 1996, 16(3): 1247-1255.
[4].  Winski S, Humphries M, Yeh T, et al. Activity of ARRY-614, an inhibitor of p38 map kinase and angiogenic targets, in hematologic malignancies. Cancer Research, 2009, 69(9 Supplement): 331-331.