Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity
Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity
复制标题
DOI：
10.1021/jm060199b
复制
发表时间：
2006-06-15
影响因子：
7.3
通讯作者：
Trevillyan, James M.
中科院分区：
文献类型：
--
作者：
Szczepankiewicz, Bruce G.;Kosogof, Christi;Trevillyan, James M.
c-Jun N-末端激酶（JNK-1、-2和-3）是丝裂原活化蛋白（MAP）激酶家族的成员。它们响应于某些细胞因子以及细胞应激（包括化学毒素、过氧化物和辐射）而被激活。它们与包括哮喘、中风、阿尔茨海默病和2型糖尿病在内的多种不同的具有炎性成分的疾病的病理学有关。在这项工作中，高通量筛选确定了一个JNK抑制剂具有良好的激酶选择性。使用X射线晶体学和生物化学筛选来指导我们的铅优化，我们制备了具有低两位数纳摩尔范围内的抑制效力、在全细胞中的活性和适合于体内使用的药代动力学的化合物。这些新化合物对JNK-1和JNK-2的选择性是其他MAP激酶（包括ERK 2、p38 α和p38 δ）的1000倍以上，对一组74种激酶几乎没有抑制活性。
The c-Jun N-terminal kinases ( JNK-1, -2, and -3) are members of the mitogen activated protein ( MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38 alpha, and p38 delta and showed little inhibitory activity against a panel of 74 kinases.