Dual binding site inhibitors of B-RAF kinase.
Computer aided modeling guided the design of a series of diarylimidazole compounds (11-22) intended to interact with both the ATP and adjacent allosteric binding domains of B-RAF kinase. Their ability to inhibit the function of B-RAF kinase and intracellular ERK1/2 phosphorylation were evaluated.
Wolin
Ronald L
RL
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. RWOLIN@PRDUS.JNJ.COM
Bembenek
Scott D
SD
Wei
Jianmei
J
Crawford
Shelby
S
Lundeen
Katherine
K
Brunmark
Anders
A
Karlsson
Lars
L
Edwards
James P
JP
Blevitt
Jonathan M
JM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000495:Allosteric Site; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D006841:Hydrocarbons, Aromatic; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases