Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes.

Angell, R.M., Angell, T.D., Bamborough, P., Bamford, M.J., Chung, C.W., Cockerill, S.G., Flack, S.S., Jones K.L., Laine, D.I., Longstaff, T., Ludbrook, S., Pearson, R., Smith. K.J., Smee, P.A., Somers, D.O., Walker, A.L.
Journal   Bioorg Med Chem Lett
Analytes Measured   HSP27 , p38
Matrix Tested   Lung fibroblast (HLF) cell lysates
Year   2008
Volume   18
Page Numbers   4433-4437
Application   Phosphoproteins
The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.

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