Synthesis and Preliminary Evaluation of Novel Isoprenylcysteine Carboxyl Methyltransferase (Icmt) Inhibitors
MacDougall, Daniel D.
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Isoprenylcysteine carboxyl methyltransferase (Icmt) is a membrane protein that catalyzes the post-translational a-carboxylmethylesterification of proteins terminating in a CAAX box sequence, including the oncoprotein Ras. This modification is crucial for the proper cellular localization and transforming ability of Ras. As a result, Icmt has recently been identified as a molecular target for anti-cancer drug design efforts. This study represents an attempt to elucidate information regarding the substrate binding site of Icmt, of which little is currently known. To do so, seven molecules were synthesized based on AFC (N-acetyl-S-famesyl-L-cysteine), the minimal synthetic substrate for Icmt. Five ofthe compounds contain aminoacyl modifications on the parent molecule, while the other two contain modifications on the famesyl chain. These compounds were tested as in vitro substrates for the human form of Icmt (hlcmt), which had been overexpressed in yeast. They were shown to act as hIcmt substrates to varying degrees. Four of the compounds were further screened as inhibitors ofhlcmt in vitro. Each was found to be a potent hlcmt inhibitor, with ICso concentrations in the micromolar region.