Abstract
In this paper we describe the synthesis of a family of CAAL peptidomimetics as GGTase-I inhibitors. These inhibitors lack the central dipeptide AA in the key CAAL carboxy terminal sequence of geranylgeranylated proteins and are more selective for GGTase-I over FTase. In whole cells, these compounds are very potent inhibitors of the processing of the geranylgeranylated protein Rap1A without affecting the farnesylated protein H-Ras. One derivative, GGTI-298, inhibited cell division by blocking cells in the G1 phase of the cell cycle.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells / drug effects
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3T3 Cells / enzymology
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Alkyl and Aryl Transferases / metabolism
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Animals
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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GTP-Binding Proteins / metabolism
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Mice
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Oligopeptides / chemical synthesis*
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Oligopeptides / pharmacology*
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Protein Prenylation
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Structure-Activity Relationship
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rap GTP-Binding Proteins
Substances
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Enzyme Inhibitors
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Oligopeptides
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Alkyl and Aryl Transferases
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geranylgeranyltransferase type-I
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GTP-Binding Proteins
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rap GTP-Binding Proteins