Author/Authors :
Richard M. Angell، نويسنده , , Tony D. Angell، نويسنده , , Paul Bamborough، نويسنده , , Mark J. Bamford، نويسنده , , Chun-wa Chung، نويسنده , , Stuart G. Cockerill، نويسنده , , Stephen S. Flack، نويسنده , , Katherine L. Jones، نويسنده , , Dramane I. Lainé، نويسنده , , Timothy Longstaff، نويسنده , , Steve Ludbrook، نويسنده , , Rosannah Pearson، نويسنده , , Kathryn J. Smith، نويسنده , , Penny A. Smee، نويسنده , , Don O. Somers، نويسنده , , Ann L. Walker، نويسنده ,
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.
Keywords :
DFG-out , MAP kinase , Selectivity , Biphenyl amide , Protein kinase X-ray structure , Kinetics , p38 Kinase inhibitors , binding mode
