title: Identification of novel 3,5-diarylpyrazoline derivatives containing salicylamide moiety as potential anti-melanoma agents.
abstract: There is an accumulating body of experimental evidences validating oncogenic BRAF(V600E) as a therapeutic target and offering opportunities for anti-melanoma drug development. Encouraged by the positive results of pyrazole derivatives as BRAF(V600E) inhibitors, we sought to design diverse novel potential BRAF(V600E) inhibitors as antitumor agents based on pyrazole skeleton. In silico and in vitro screening of our designed pyrazole derivatives has identified Hit 1 as BRAF(V600E) inhibitor. Based on its structure and through further structure modification, compound 25, which exhibited the most potent inhibitory activity with an IC(50) value of 0.16 μM for BRAF(V600E) and GI(50) value of 0.24 μM for mutant BRAF-dependent melanoma cells, was obtained. The 3D-QSAR models and the molecular docking simulation were introduced to analyze the structure-activity relationship.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Li
authors.forename: Xian-Hai
authors.initials: XH
authors.lastname: Lv
authors.forename: Yan-Bin
authors.initials: YB
authors.lastname: Zhang
authors.forename: Jing-Jun
authors.initials: JJ
authors.lastname: Dong
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012457:Salicylamides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D012457:Salicylamides; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C031060:salicylamide