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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Design, Synthesis and Antitumor Activities of Bis-arylureas and Bis-arylamides Based on1H-benzo[d]imidazole Moiety as Novel BRafV600E/VEGFR2 Dual inhibitors

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

Volume 11, Issue 9, 2014

Page: [1079 - 1089] Pages: 11

DOI: 10.2174/1570180811666140724184806

Price: $65


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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