Design and biological evaluation of novel triaryl pyrazoline derivatives with dioxane moiety for selective BRAF inhibition.

A series of novel selective BRAF inhibitory agents (Compound 1-16) 5-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)-N,3-diaryl-4,5-dihydro-1H-pyrazole-1-carbothioamides have been designed and synthesized. Their anti-proliferation and BRAF inhibitory activities were evaluated. Though 15, 4 and 12 all displayed comparable activity with the positive control Vemurafenib, only 12 indicated fine selectivity on BRAF (IC50 = 0.06 μM for BRAF; GI50 = 0.52 μM for A375) over BRAF at both kinase and cell levels. This result satisfied the designing concept of improving activity and introducing selectivity. Flow cytometry analysis and western blot convinced the apoptosis induction and kinase inhibitory activity. Docking simulation inferred the differences in binding patterns of BRAF and BRAF, pointing out that the future orientation might be seeking for outer space binding of BRAF and avoiding interactions with HIS573 of BRAF. These results brought potent BRAF inhibitors one step further to selective agents, enhancing the potential for safe medication.