X-ray crystal structure of JNK2 complexed with the p38α inhibitor BIRB796: Insights into the rational design of DFG-out binding MAP kinase inhibitors
✍ Scribed by Andreas Kuglstatter; Manjiri Ghate; Stan Tsing; Armando G. Villaseñor; David Shaw; Jim W. Barnett; Michelle F. Browner
- Publisher
- Elsevier Science
- Year
- 2010
- Tongue
- English
- Weight
- 669 KB
- Volume
- 20
- Category
- Article
- ISSN
- 0960-894X
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✦ Synopsis
JNK2 and p38a 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 p38a 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.