Abstract
A series of novel diaryl ether lactams have been identified as very potent dual inhibitors of protein farnesyltransferase (FTase) and protein geranylgeranyltransferase I (GGTase-I), enzymes involved in the prenylation of Ras. The structure of the complex formed between one of these compounds and FTase has been determined by X-ray crystallography. These compounds are the first reported to inhibit the prenylation of the important oncogene Ki-Ras4B in vivo. Unfortunately, doses sufficient to achieve this endpoint were rapidly lethal.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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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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Carrier Proteins / metabolism
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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HSP40 Heat-Shock Proteins
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Heat-Shock Proteins / metabolism
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Humans
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Mice
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Mice, Nude
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Models, Molecular
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Neoplasm Transplantation
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Neoplasms, Experimental / drug therapy
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Protein Prenylation
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Structure-Activity Relationship
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Transplantation, Heterologous
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Tumor Cells, Cultured
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rap1 GTP-Binding Proteins / metabolism
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ras Proteins / metabolism
Substances
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Antineoplastic Agents
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Carrier Proteins
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DNAJA1 protein, human
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HSP40 Heat-Shock Proteins
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Heat-Shock Proteins
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Alkyl and Aryl Transferases
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geranylgeranyltransferase type-I
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p21(ras) farnesyl-protein transferase
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rap1 GTP-Binding Proteins
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ras Proteins