Protein prenylation is a post-translational modification controlling the localization, activity, and protein–protein interactions of small GTPases, including the Ras superfamily. This covalent attachment of either a farnesyl (15 carbon) or a geranylgeranyl (20 carbon) isoprenoid group is catalyzed by four prenyltransferases, namely farnesyltransferase (FTase), geranylgeranyltransferase type I (GGTase-I), Rab geranylgeranyltransferase (GGTase-II), and recently discovered geranylgeranyltransferase type III (GGTase-III). Blocking small GTPase activity, namely inhibiting prenyltransferases, has been proposed as a potential disease treatment method. Inhibitors of prenyltransferase have resulted in substantial therapeutic benefits in various diseases, such as cancer, neurological disorders, and viral and parasitic infections. In this review, we overview the structure of FTase, GGTase-I, GGTase-II, and GGTase-III and summarize the current status of research on their inhibitors.
Rab geranylgeranyl transferase (RGGT) is an interesting therapeutic target, as it ensures proper functioning of Rab GTPases, a class of enzymes responsible for the regulation of vesicle trafficking. Relying on our previous studies, we synthesized a set of new α-phosphonocarboxylic acids as potential RGGT inhibitors, with emphasis on the elaboration of imidazole-containing analogues. We identified two compounds with activity similar to that of previously reported RGGT inhibitors, showing structural similarity to imidazo[1,2-a]pyridine-containing analogues in terms of their substitution pattern. Interestingly, analogues of the N-series, derived from another phosphonocarboxylate RGGT inhibitor, 2-fluoro-3-(1H-imidazol-1-yl)-2-phosphonopropanoic acid, turned out to be inactive in our model, indicating that an additional substituent localized at positions C2 or C4 of the imidazole ring, may adversely affect the potency against the targeted enzyme.
Twelve phosphonopropionates derived from 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC) were synthesized and evaluated for their activity as inhibitors of protein geranylgeranylation. The nature of the substituent in the C6 position of imidazo[1,2-a]pyridine ring was responsible for the compound's activity against Rab geranylgeranyl transferase (RGGT). The most active inhibitors disrupted Rab11A prenylation in the human cervical carcinoma HeLa cell line. The esterification of carboxylic acid in the phosphonopropionate moiety turned the inhibitor into an inactive analog.
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