Protein Farnesyltransferase Inhibitors
Pp. 97-128 (32)
Semiramis Ayral-Kaloustian and Edward J. Salaski
Specific mutations in the ras gene impair the guanosine triphophatase (GTPase) activity of Ras proteins, which play a fundamental role in the signaling cascade, leading to uninterrupted growth signals and to the transformation of normal cells into malignant phenotypes. It has been shown that normal cells transfected with mutant ras gene become cancerous and that unfarnesylated, cytosolic mutant Ras protein does not anchor onto cell membranes and cannot induce this transformation. Posttranslational modification and plasma membrane association of mutant Ras is necessary for this transforming activity. Since its identification, the enzyme protein farnesyltransferase (FTase) that catalyzes the first and essential step of the three Ras processing steps has emerged as the most promising target for therapeutic intervention. FTase has been implicated as a potential target in inhibiting the prenylation of a variety of proteins, thus in controlling varied disease states (e.g. cancer, neurofibromatosis, restenosis, viral hepatitis, bone resorption, parasitic infections, corneal inflammations, and diabetes) associated with prenyl modifications of Ras and other proteins. Furthermore, it has been suggested that FTase inhibitors indirectly help in inhibiting tumors via suppression of angiogenesis and induction of apoptosis. Major milestones have been achieved with small-molecule FTase inhibitors that show efficacy without toxicity in vitro, as well as in mouse models bearing ras-dependent tumors. With the determination of the crystal structure of mammalian FTase, existent leads have been fine-tuned and new potent molecules of diverse structural classes have been designed. Extensive in vitro and in vivo studies with these inhibitors have revealed the complexities of the signaling cascade involving FTase, and shed more light on possible modes of tumor inhibition, without providing a clear-cut mechanism of action. A few of these molecules are currently in the clinic, with at least three drug candidates in Phase II studies and two in Phase III. This article will review the progress that has been reported with FTase inhibitors in drug discovery and in the clinic.
Wyeth Research, Pearl River, NY 10965-1299, USA