DESIGN OF DUAL ALLOSTERIC INHIBITORS OF B-RAF AND C-RAF KINASES FOR CANCER TREATMENT

Abstract

We present a computational design of new, druglike small molecules that could allosterically inhibit both B-Raf and C-Raf kinases. The Raf kinases stimulate activators of MAPK pathways. MAPK pathways participates in cell proliferation and apoptosis. Mutations of the proteins in the pathway have been implicated in cancers. Many cancer drugs are MAPK inhibitors (MAPKi). Although MAPKi decrease cancer growth, bypass signaling is often formed. Consequently, most patients develop MAPKi resistance within a year. Most kinase inhibitors bind to the kinase catalytic site. These sites are similar in many kinases, making it challenging to target them specifically. Allosteric sites differ between kinases, permitting selective binding. Catalytic-site B-Raf inhibitors can successfully restrain the kinase in cancers with mutated B-Raf. However, they also promote dimerization of B-Raf with either itself or C-Raf. This can increase the C-Raf activation if an upstream Raf-activator is mutated. A simultaneous inhibition of both B-Raf and C-Raf is needed to avoid the development of cancer treatment resistance. The Deep View program was used to analyze the B-Raf and C-Raf binding sites. New putative small-molecule inhibitors were designed by systematically modifying the known inhibitors. The DataWarrior and Molinspiration programs were used to calculate the druglike properties of the designed molecules. Molecules with optimal druglike properties and no indicated toxic risks were docked to B-Raf and C-Raf using the ArgusLab program. The binding energies of stable complexes were calculated. Three designed molecules had better druglike properties and bound allosterically both B-Raf and C-Raf with higher binding energies than known inhibitors did. Our work, coupled with prior experimental studies, suggest that the molecules designed here may be potent allosteric inhibitors of both B-Raf and C-Raf. They may achieve increased therapeutic response in tumors with either B-Raf mutations or mutations of upstream activators of Raf.
Keywords: Druglike Small Molecules, Allosteric Inhibitors, Raf Kinases.