title: 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.
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.
authors.affiliation: School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Yang
authors.affiliation: School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Gu
authors.affiliation: School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Qian
authors.affiliation: School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: 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.
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.affiliation: School of Basic Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China. Electronic address: twf@cpu.edu.cn.
authors.forename: Weifang
authors.initials: W
authors.lastname: Tang
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000600799:3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-N-(4-chloro-3-methylphenyl)-4-methylbenzamide; D000577:Amides; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011687:Purines; D014508:Urea; D048493:Proto-Oncogene Proteins B-raf
keywords: Antitumor agents; B-Raf inhibitors; DFG-Out; Melanoma