1016837-54-9Relevant articles and documents
Design, synthesis and biological evaluation of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine scaffold as DFG-out B-Raf kinase inhibitors
Yang, Weimin,Chen, Yadong,Zhou, Xiang,Gu, Yazhou,Qian, Wenqi,Zhang, Fan,Han, Wei,Lu, Tao,Tang, Weifang
, p. 581 - 596 (2014/12/12)
By combining the scaffolds of UI-125 and Sorafenib, a series of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine moiety were designed and synthesized as novel DFG-out B-RafV600E inhibitors. Among them, 20c-e, 20g and 21h displayed potent antiproliferative activities against melanoma A375 (B-RafV600E) cell lines with IC50 values of 3.190, 2.276, 1.856, 1.632 μM and 1.839 μM, respectively, comparable with the positive control Vemurafenib (IC50 Combining double low line 3.32 μM). Selected compounds were tested for the ERK inhibition in human melanoma A375 (B-RafV600E) and SK-MEL-2 (B-RafWT) cell lines by Western blot. The results revealed that our compounds inhibited the proliferation of melanoma A375 cells (B-RafV600E) through ERK pathway, without paradoxical activation of ERK in melanoma SK-MEL-2 cells (B-RafWT). Eventually, 20g and 21h were selected to confirm their inhibitory effects on tumor growth in A375 xenograft models in mice. Compound 20g exhibited equivalent antitumor efficacy in vivo (T/C Combining double low line 44.37%), compared to Sorafenib (T/C Combining double low line 37.35%), by 23-day repetitive administration of a single dose of 50 mg/kg without significant body weight loss.
