Pharmacophore and Binding Analysis of Known and Novel B-RAF Kinase Inhibitors
F. Baska, I. Szabadkai, A. Sipos, N. Breza, C. Szantai-Kis, L. Kekesi, R. Garamvolgyi, Z. Nemes, F. Baska, L. Neumann, R. Torka, A. Ullrich, G. Keri and L. Orfi
Affiliation: Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes Endre utca 9. H-1092, Budapest, Hungary.
The extensively investigated serine/threonine kinase, B-RAF, is a member of the RAS/RAF/MEK/ERK pathway.
It plays important role in the regulation of cell growth, differentiation and survival. The mutation of B-RAF occurs
frequently in melanomas and colon tumors; therefore, it is considered as an outstanding therapeutic target. In recent years
a great number of B-RAF inhibitors have been reported and this number is expected to increase. The aim of our work was
to compare the structures and binding mode of the published B-RAF inhibitors, and then to apply the correlations found
for the explanation of our experimental results. In the first part of this paper we describe the main pharmacophore features
of the co-crysallized B-RAF inhibitors published in the literature, focusing on the binding modes and common structural
elements. In the second part we present and characterize our recently developed B-RAF inhibitor family by application of
in silico methods and in vitro kinetic profiling. The inhibitory activity of these compounds was determined in biochemical
kinase- and cell-based assays. The docking and assay results support our conclusion that the presented compound family
belongs to the type I 1/2subgroup, they inhibit B-RAF and B-RAF(V600E) mutant in a sub-micromolar range and most of
them show selectivity towards B-RAF(V600E) mutant expressing cell lines with equal or even better IC50 values than
Keywords: Binding mode, B-RAF, docking, kinase assay, kinase inhibitor, kinetic profiling.
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