2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2015 Jan 7:89:581-96. doi: 10.1016/j.ejmech.2014.10.039.
Weimin Yang 1,  Yadong Chen 1,  Xiang Zhou 1,  Yazhou Gu 1,  Wenqi Qian 1,  Fan Zhang 1,  Wei Han 1,  Tao Lu 2,  Weifang Tang 3
Affiliations

Affiliations

  • 1 School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
  • 2 School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, China. Electronic address: lutao@cpu.edu.cn.
  • 3 School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China. Electronic address: twf@cpu.edu.cn.
PMID: 25462267 DOI: 10.1016/j.ejmech.2014.10.039
Abstract

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-Raf(V600E) inhibitors. Among them, 20c-e, 20g and 21h displayed potent antiproliferative activities against melanoma A375 (B-Raf(V600E)) 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 = 3.32 μM). Selected compounds were tested for the ERK inhibition in human melanoma A375 (B-Raf(V600E)) and SK-MEL-2 (B-Raf(WT)) cell lines by Western blot. The results revealed that our compounds inhibited the proliferation of melanoma A375 cells (B-Raf(V600E)) through ERK pathway, without paradoxical activation of ERK in melanoma SK-MEL-2 cells (B-Raf(WT)). 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 = 44.37%), compared to Sorafenib (T/C = 37.35%), by 23-day repetitive administration of a single dose of 50 mg/kg without significant body weight loss.

Keywords

Antitumor agents; B-Raf inhibitors; DFG-Out; Melanoma.

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