X-ray crystal structure of JNK2 complexed with the p38alpha inhibitor BIRB796: insights into the rational design of DFG-out binding MAP kinase inhibitors.
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.
Kuglstatter
Andreas
A
Roche Palo Alto, Palo Alto, CA 94304, USA. andreas.kuglstatter@roche.com
Ghate
Manjiri
M
Tsing
Stan
S
Villaseñor
Armando G
AG
Shaw
David
D
Barnett
Jim W
JW
Browner
Michelle F
MF
D018360:Crystallography, X-Ray; D015195:Drug Design; D048056:Mitogen-Activated Protein Kinase 9 / Q000737:chemistry*; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010671:Phenylurea Compounds
D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048051:p38 Mitogen-Activated Protein Kinases; C452139:doramapimod; D010671:Phenylurea Compounds