3npc

Publication Abstract from PubMed

JNK2 and p38alpha 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 p38alpha 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 p38alpha 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.

X-ray crystal structure of JNK2 complexed with the p38alpha inhibitor BIRB796: insights into the rational design of DFG-out binding MAP kinase inhibitors.,Kuglstatter A, Ghate M, Tsing S, Villasenor AG, Shaw D, Barnett JW, Browner MF Bioorg Med Chem Lett. 2010 Sep 1;20(17):5217-20. Epub 2010 Jul 23. PMID:20655210^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.