X-ray crystal structure of JNK2 complexed with the p38α inhibitor BIRB796: Insights into the rational design of DFG-out binding MAP kinase inhibitors

被引：30

作者：

Kuglstatter, Andreas ^{[1
]}

Ghate, Manjiri ^{[1
]}

Tsing, Stan ^{[1
]}

Villasenor, Armando G. ^{[1
]}

Shaw, David ^{[1
]}

Barnett, Jim W. ^{[1
]}

Browner, Michelle F. ^{[1
]}

机构：

[1] Roche Palo Alto, Palo Alto, CA 94304 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 17期

关键词：

JNK2; p38; BIRB796; Protein crystallography; X-ray crystal structure; DFG-out; Protein kinase; Kinase inhibitor; Structure-based drug design; N-TERMINAL KINASES; RHEUMATOID-ARTHRITIS; P38; PATHWAY;

D O I：

10.1016/j.bmcl.2010.06.157

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

JNK2 and p38 alpha are closely related mitogen-activated protein kinases that regulate various cellular activities and are considered drug targets for inflammatory diseases. We have determined the X-ray crystal structure of the clinical phase II p38 alpha inhibitor BIRB796 bound to its off-target JNK2. This shows for the first time a JNK subfamily member in the DFG-out conformation. The fully resolved activation loop reveals that BIRB796 inhibits JNK2 activation by stabilizing the loop in a position that does not allow its phosphorylation by upstream kinases. The structure suggests that substituents at the BIRB796 morpholino group and modifications of the t-butyl moiety should further increase the p38a to JNK2 potency ratio. For the design of selective DFG-out binding JNK2 inhibitors, the binding pocket of the BIRB796 tolyl group may have the best potential. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5217 / 5220

页数：4

共 27 条

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