Abstract

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-Raf^V600E/VEGFR2 dual inhibitors. Compound 4a as the most potent compound displayed potential dual kinase inhibitory activities against B-Raf^V600E 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-Raf^V600E) xenograft model by contrast to Sorafenib (T/C = 16.49%) without body weight loss.

Keywords: Antitumor, B-Raf^V600E, DFG-out type, dual inhibitors, 1H-benzo[d]imidazole moiety, VEGFR2.

Graphical Abstract