Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes.
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.
Angell
Richard M
RM
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Angell
Tony D
TD
Bamborough
Paul
P
Bamford
Mark J
MJ
Chung
Chun-wa
CW
Cockerill
Stuart G
SG
Flack
Stephen S
SS
Jones
Katherine L
KL
Laine
Dramane I
DI
Longstaff
Timothy
T
Ludbrook
Steve
S
Pearson
Rosannah
R
Smith
Kathryn J
KJ
Smee
Penny A
PA
Somers
Don O
DO
Walker
Ann L
AL
D000577:Amides / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D008070:Lipopolysaccharides / Q000494:pharmacology; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D015394:Molecular Structure; D009281:Naphthalenes / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010671:Phenylurea Compounds
D000577:Amides; D000596:Amino Acids; D001713:Biphenyl Compounds; D008070:Lipopolysaccharides; D048308:Mitogen-Activated Protein Kinase 14; D009281:Naphthalenes; D011720:Pyrazoles; C452139:doramapimod; D010671:Phenylurea Compounds