A series of bis-arylurea and bis-arylamide derivatives based on 1H-benzo[d]imidazole moiety were designed,
synthesized and evaluated as DFG-out B-RafV600E/VEGFR2 dual inhibitors. Compound 4a as the most potent compound
displayed potential dual kinase inhibitory activities against B-RafV600E and VEGFR2 with IC50 values of 57.8 nM and 0.48
μM, as well as effective cellular antiproliferative potencies against A375 and HUVEC with IC50 values of 3.62 µM and
12.46 µM. 4a was also progressed to in vivo profiling, which exhibited similarly equivalent tumor growth inhibition (T/C
= 17.99%) in human melanoma A375 (B-RafV600E) xenograft model by contrast to Sorafenib (T/C = 16.49%) without
body weight loss.
Keywords: Antitumor, B-RafV600E, DFG-out type, dual inhibitors, 1H-benzo[d]imidazole moiety, VEGFR2.
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