Dual binding site inhibitors of B-RAF kinase

Ronald L Wolin; Scott D Bembenek; Jianmei Wei; Shelby Crawford; Katherine Lundeen; Anders Brunmark; Lars Karlsson; James P Edwards; Jonathan M Blevitt

doi:10.1016/j.bmcl.2008.04.002

Dual binding site inhibitors of B-RAF kinase

Bioorg Med Chem Lett. 2008 May 1;18(9):2825-9. doi: 10.1016/j.bmcl.2008.04.002. Epub 2008 Apr 4.

Authors

Ronald L Wolin¹, Scott D Bembenek, Jianmei Wei, Shelby Crawford, Katherine Lundeen, Anders Brunmark, Lars Karlsson, James P Edwards, Jonathan M Blevitt

Affiliation

¹ Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. RWOLIN@PRDUS.JNJ.COM

PMID: 18434146
DOI: 10.1016/j.bmcl.2008.04.002

Abstract

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.

MeSH terms

Adenosine Triphosphate / metabolism
Allosteric Site
Computer-Aided Design*
Crystallography, X-Ray
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Hydrocarbons, Aromatic / chemical synthesis
Hydrocarbons, Aromatic / pharmacology*
Imidazoles / chemical synthesis
Imidazoles / pharmacology*
Inhibitory Concentration 50
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Hydrocarbons, Aromatic
Imidazoles
Protein Kinase Inhibitors
Adenosine Triphosphate
Proto-Oncogene Proteins B-raf
Extracellular Signal-Regulated MAP Kinases