Abstract
Design, synthesis and structure-activity relationship of a class of aryl pyrroles as farnesyltransferase inhibitors are described. In vitro and in vivo evaluation of a panel of these inhibitors led to identification of 2 (LB42908) as a highly potent (IC(50)=0.9 nM against H-Ras and 2.4 nM against K-Ras) antitumor agent that is currently undergoing preclinical studies.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Dose-Response Relationship, Drug
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Drug Design
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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Imidazoles / chemistry*
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Imidazoles / pharmacology*
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Inhibitory Concentration 50
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Mice
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Mice, Nude
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Peptides / chemistry
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Piperazines / chemistry*
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Piperazines / pharmacology*
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Structure-Activity Relationship
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Imidazoles
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LB42908
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Peptides
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Piperazines
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Alkyl and Aryl Transferases
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p21(ras) farnesyl-protein transferase