Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes |
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| Authors: | Angell Richard M Angell Tony D Bamborough Paul Bamford Mark J Chung Chun-wa Cockerill Stuart G Flack Stephen S Jones Katherine L Laine Dramane I Longstaff Timothy Ludbrook Steve Pearson Rosannah Smith Kathryn J Smee Penny A Somers Don O Walker Ann L |
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| Affiliation: | aGlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK |
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| Abstract: | The biphenyl amides (BPAs) are a series of p38α 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 p38α 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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| Keywords: | p38 Kinase inhibitors MAP kinase Biphenyl amide Protein kinase X-ray structure Binding mode DFG-out Selectivity Kinetics |
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