کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1374655 | 981922 | 2010 | 4 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: X-ray crystal structure of JNK2 complexed with the p38α inhibitor BIRB796: Insights into the rational design of DFG-out binding MAP kinase inhibitors X-ray crystal structure of JNK2 complexed with the p38α inhibitor BIRB796: Insights into the rational design of DFG-out binding MAP kinase inhibitors](/preview/png/1374655.png)
JNK2 and p38α 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 p38α 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 p38α 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.
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Journal: Bioorganic & Medicinal Chemistry Letters - Volume 20, Issue 17, 1 September 2010, Pages 5217–5220