The Design, Synthesis And Bioactivity Of B-Raf^V600E Kinase Inhibitors

Cancer is one of the diseases that commonly seen and threaten human lives, its mortality is very high and only second to cardiovascular disease. The Ras-Raf-MEK-ERK signal pathway which is mediated by Raf kinase has a significant role in the formation of tumor. It has been revealed that about8%of all human tumors are related to mutant B-Raf kinase, especially at the residue600, the valine to glutamic acid, which occupies almost90%in all mutant B-Raf kinases. So, the finding of novel B-RafV600E kinase inhibitors has a vital role in B-RafV600E related tumor treatment.In this research, virtual screening, molecule design and modification, chemical synthesis and bioactivity were used in finding a series of novel N-(thiophen-2-yl) benzamide derivatives that possess B-RafV600E inhibitory abilities. And the structure activity relationships of them were summarized.Firstly, Receptor based virtual screening (RBVS) was used in finding a hit compound al (IC50=2.01μM) that possess B-RafV600E inhibitory ability, then a reversed search through the SPECS data bank was committed and21derivatives of al, a2-a22were found and bought, then, their inhibitory ability towards B-RafV600E were tested. The results showed that compound a6possess better inhibitory ability, with an IC5o value about1.16μM, and the binding mode was analyzed by docking into its receptor3OG7. Then, based on bioisostere theory, the binding mode and structures of b23-b47, b series compounds were design and synthesized. Compounds b40and b47in b series possessess good inhibitory ability towards B-RafV600E, the IC50of them were0.77μM and0.63μM respectively. Finally, kinase selectivity experiment was done and the result shows that the compounds have a good selectivity toward B-RafV600E kinase...