Design, synthesis, and biological evaluation of pyrazole derivatives containing acetamide bond as potential BRAFV600E inhibitors.

With the increasingly acquired resistance, relapse and side effects of known marketed BRAFV600E inhibitors, it's significant to design the more effective and novel drugs. In this study, a series of novel pyrazole derivatives containing acetamide bond had been designed and synthesized on the basis of analysis of the endogenous ligands extracted from the known B-Raf co-crystals in the PDB database. Then, the compounds were evaluated for biological activities as potential BRAFV600E inhibitors. The bioassay results in vitro against three human tumor cell lines revealed that some of the compounds showed very impressed antiproliferative property. Among them, the compound 5r with IC50 values of 0.10 ±â€¯0.01 µM against BRAFV600E and 0.96 ±â€¯0.10 µM against A375 cell line, showed the most potent inhibitory effect, compared with the positive-controlled agents vemurafenib (IC50 = 0.04 ±â€¯0.004 µM for BRAFV600E, IC50 = 1.05 ±â€¯0.10 µM against A375). Further investigation confirmed that the compound 5r could induce A375 cell apoptosis, induce A375 cell death through changing mitochondrial membrane potential, and result in A375 cell arrest at the G1 phase of the cell cycle. Docking simulations results indicated that the compound 5r could bind tightly at the BRAFV600E active site. Meanwhile, 3D-QSAR model suggested that these compounds may be potential anticancer inhibitors. Overall, the article provided some new molecular scaffolds for the further BRAFV600E inhibitors.