Szczepankiewicz Bruce G, Kosogof Christi, Nelson Lissa T J, Liu Gang, Liu Bo, Zhao Hongyu, Serby Michael D, Xin Zhili, Liu Mei, Gum Rebecca J, Haasch Deanna L, Wang Sanyi, Clampit Jill E, Johnson Eric F, Lubben Thomas H, Stashko Michael A, Olejniczak Edward T, Sun Chaohong, Dorwin Sarah A, Haskins Kristi, Abad-Zapatero Cele, Fry Elizabeth H, Hutchins Charles W, Sham Hing L, Rondinone Cristina M, Trevillyan James M
Metabolic Disease Research, Global Pharmaceutical Research and Discovery Organization, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6098, USA.
J Med Chem. 2006 Jun 15;49(12):3563-80. doi: 10.1021/jm060199b.
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 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases.
c-Jun氨基末端激酶（JNK-1、-2和-3）是丝裂原活化蛋白（MAP）激酶家族的成员。它们可因某些细胞因子以及包括化学毒素、过氧化物和辐射在内的细胞应激而被激活。它们与多种具有炎症成分的不同疾病的病理过程有关，包括哮喘、中风、阿尔茨海默病和2型糖尿病。在这项工作中，高通量筛选鉴定出一种具有优异激酶选择性谱的JNK抑制剂。利用X射线晶体学和生化筛选来指导我们的先导化合物优化，我们制备出了抑制效力在低两位数纳摩尔范围内、在全细胞中有活性且药代动力学适合体内使用的化合物。这些新化合物对JNK-1和-2的选择性比对包括ERK2、p38α和p38δ在内的其他MAP激酶高1000多倍，并且对一组74种激酶几乎没有抑制活性。
