A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity.

Abstract

Inhibiting protein prenylation is an attractive means to modulate cellular processes controlled by a variety of signaling proteins, including oncogenic proteins such as Ras and Rho GTPases. The largest class of prenylated proteins contain a so-called CaaX motif at their carboxyl termini and are subject to a maturation process initiated by the attachment of an isoprenoid lipid by either protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I (GGTase-I). Inhibitors of FTase, termed FTIs, have been the subject of intensive development in the past decade and have shown efficacy in clinical trials. Although GGTase-I inhibitors (GGTIs) have received less attention, accumulating evidence suggests GGTIs may augment therapies using FTIs and could be useful to treat a myriad of additional disease states. Here we describe the characterization of a selective, highly potent, and cell-active GGTase-I inhibitor, GGTI-DU40. Kinetic analysis revealed that inhibition by GGTI-DU40 is competitive with the protein substrate and uncompetitive with the isoprenoid substrate; the Ki for the inhibition is 0.8 nM. GGTI-DU40 is highly selective for GGTase-I both in vitro and in living cells. Studies indicate GGTI-DU40 blocks prenylation of a number of geranylgeranylated CaaX proteins. Treatment of MDA-MB-231 breast cancer cells with GGTI-DU40 inhibited thrombin-induced cell rounding via a process that involves inhibition of Rho proteins without significantly effecting parallel mobilization of calcium via Gbetagamma. These studies establish GGTI-DU40 as a prime tool for interrogating biologies associated with protein geranylgeranylation and define a novel structure for this emerging class of experimental therapeutics.

• Authors: Yuri K Peterson, Patrick Kelly, Carolyn A Weinbaum, Patrick J Casey
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 18 Pg. 12445-50 (May 05 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16517596 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Lipids
• Alkyl and Aryl Transferases
• geranylgeranyltransferase type-I
• p21(ras) farnesyl-protein transferase
• rap1 GTP-Binding Proteins

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors, chemistry)
• Amino Acid Motifs
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Dogs
• Drug Design
• Enzyme Inhibitors (pharmacology)
• Humans
• Lipids (chemistry)
• Signal Transduction
• rap1 GTP-Binding Proteins (metabolism)