Abstract
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Biological Availability
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Crystallography, X-Ray
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Drug Design
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Melanoma, Experimental / drug therapy
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Melanoma, Experimental / enzymology
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Melanoma, Experimental / pathology
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Mice
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Mice, Nude
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Models, Molecular
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Mutation
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / genetics
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Stereoisomerism
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Structure-Activity Relationship
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Tetrahydronaphthalenes / chemical synthesis*
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Tetrahydronaphthalenes / chemistry
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Tetrahydronaphthalenes / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Tetrahydronaphthalenes
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Proto-Oncogene Proteins B-raf