Document Report Card

ID: ALA1132630

Journal: J Med Chem

Title: Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I.

Authors: Vasudevan A, Qian Y, Vogt A, Blaskovich MA, Ohkanda J, Sebti SM, Hamilton AD.

Abstract: The design, synthesis, and biological evaluation of a family of peptidomimetic inhibitors of protein geranylgeranyltransferase-I (PGGTase-I) are reported. The inhibitors are based on the C-terminal CAAL sequence of many geranylgeranylated proteins. Using 2-aryl-4-aminobenzoic acid derivatives as mimetics for the central dipeptide (AA), we have attached a series of imidazole and pyridine derivatives to the N-terminus as cysteine replacements. These non-thiol-containing peptidomimetics show exceptional selectivity for PGGTase-I over the closely related enzyme protein farnesyltransferase (PFTase). This selectivity is retained in whole cells where the inhibitors were shown to block the geranylgeranylation of Rap-1A without affecting the farnesylation of small GTP-binding proteins such as Ras.

CiteXplore: 10212118

DOI: 10.1021/jm9900873