title: Design, synthesis and biological evaluation of novel (E)-α-benzylsulfonyl chalcone derivatives as potential BRAF inhibitors.
abstract: Activating mutations in the BRAF serine/threonine kinase are found in more than 70% of human melanomas, >90% of which are BRAF(V600E). It provides new therapeutic opportunities in malignant melanoma. In silico and in vitro screening of our compound collection has identified Hit 2 as BRAF(V600E) inhibitor. Based on its structure, a series of novel (E)-α-benzylsulfonyl chalcone derivatives (13-40) were designed and synthesized. Compound 38 exhibited the most potent inhibitory activity with an IC(50) value of 0.17 μM for BRAF(V600E) and GI(50) value of 0.52 μM for mutant BRAF-dependent cells. The results of cell based pERK activity and cellular selectivity suggested that those compounds could selectively inhibit proliferation of mutant BRAF-dependent melanoma cell line through inhibition of oncogenic BRAF.
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: Cui-Yun
authors.initials: CY
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Lu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000737:chemistry*; D047188:Chalcones / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy*; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: C573630:2-(4-chlorobenzylsulfonyl)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one; D047188:Chalcones; D047428:Protein Kinase Inhibitors; D013450:Sulfones; D002599:Chalcone; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf