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.
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chalcone / chemistry*
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Chalcones / chemical synthesis*
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Chalcones / pharmacology*
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Drug Design*
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Drug Screening Assays, Antitumor
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Humans
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Inhibitory Concentration 50
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Melanoma / drug therapy*
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Molecular Structure
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Mutation / genetics
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / chemistry
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Proto-Oncogene Proteins B-raf / genetics
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / pharmacology*
Substances
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2-(4-chlorobenzylsulfonyl)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one
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Chalcones
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Protein Kinase Inhibitors
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Sulfones
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Chalcone
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BRAF protein, human
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Proto-Oncogene Proteins B-raf