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2008
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Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes.
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.
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Journal
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Bioorg Med Chem Lett
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Species
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Analytes Measured
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HSP27
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p38
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Matrix Tested
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Lung fibroblast (HLF) cell lysates
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Abstract
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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