Design, Synthesis and Antitumor Activities of Bis-arylureas and Bis-arylamides Based on1H-benzo[d]imidazole Moiety as Novel BRaf^V600E/VEGFR2 Dual inhibitors

Title:Design, Synthesis and Antitumor Activities of Bis-arylureas and Bis-arylamides Based on1H-benzo[d]imidazole Moiety as Novel BRaf^V600E/VEGFR2 Dual inhibitors

Volume: 11 Issue: 9

Author(s): Weimin Yang, Yadong Chen, Yanmin Zhang, Sanzhi Tang, Hongli Chen, Weifang Tang and Tao Lu

Affiliation:

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

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.

Cite this article as:

Yang Weimin, Chen Yadong, Zhang Yanmin, Tang Sanzhi, Chen Hongli, Tang Weifang and Lu Tao, Design, Synthesis and Antitumor Activities of Bis-arylureas and Bis-arylamides Based on1H-benzo[d]imidazole Moiety as Novel BRaf^V600E/VEGFR2 Dual inhibitors, Letters in Drug Design & Discovery 2014; 11(9) . https://dx.doi.org/10.2174/1570180811666140724184806