Non-Peptidic Prenyltransferase Inhibitors: Diverse Structural Classes and Surprising Anti-Cancer Mechanisms

Abstract

The development of farnesyltransferase inhibitors (FTIs) has been one of the most active areas of anticancer drug development for the past ten years. This review presents a general overview of the developments in this area, along with a critical appraisal of the anticancer activity of FTIs. A historical survey of the protein prenylation field is given, in particular to emphasize the key role played by the Ras oncoprotein in driving the discovery of prenyltransferase enzymes. The different classes of prenylated proteins will be described along with the biochemical characteristics of the key drug target--farnesyltransferase (FTase). Numerous potent farnesyltransferase inhibitors have been developed. The FTIs developed can be separated into three different categories, based on their origin and/or mechanism of action: a) natural products; b) peptidomimetics and other CAAX-competitive inhibitors; c) farnesyl pyrophosphate (FPP) mimetics or analogs and other FPP-competitive inhibitors. Along with a survey of newer FTIs in each class, the development of several representative, potent compounds will be discussed in depth as we discuss the potential advantages and liabilities of each class. Particular emphasis is given to the discovery of new, more potent FPP-competitive FTIs of several diverse structural classes. Testing of different FTIs for their ability to block the growth of various cancer cell types in animal models will be discussed. There are a number of key differences between these compounds and traditional cytotoxic cancer chemotherapeutic agents, with surprising exceptions to their expected modes of action. As some FTIs have entered human clinical trials, answers may soon become available to key mechanistic questions concerning the extent and nature of their antitumor growth properties.

Farnesyl Transferase Inhibitors: Mechanism of Action, Translational Studies and Clinical Evaluation

“…[29][30][31][32][33][34] The peptidomimetic compound L-778,123 has undergone clinical testing. 35 Several FTIs have been reported to be competitive with the farnesyl diphosphate substrate 36 or are bisubstrate analogs incorporating structural features of both farnesyl diphosphate and the CAAX tetrapeptide. 37 Other FTIs were identified by screening of chemical libraries followed by medicinal chemistry optimization, including the tricyclic compound SCH 66336 and its analogs, 38,39 R115777, 40 and BMS-214662.…”

Induction of Apoptosis in Neurofibromatosis Type 1 Malignant Peripheral Nerve Sheath Tumor Cell Lines by a Combination of Novel Farnesyl Transferase Inhibitors and Lovastatin

“…This membrane attachment requires numerous post-translational modifications. The initial step is the covalent addition of a 15C far- jpet.aspetjournals.org nesyl or a 20C geranylgeranyl group to the cysteine located on the C-terminal CaaX box (Gibbs et al, 2001). This modification is critical for proper Ras function and has been investigated as a potential target for treating NF1 MPNST cells.…”

“…Ras proteins are translated as inactive precursor molecules that must undergo a series of post-translational modifications before becoming fully functional (Gibbs et al, 2001). The first necessary step is the covalent addition of a prenyl group, either a 15C farnesyl or a 20C geranylgeranyl group, to the C-terminal "CaaX" box (Basso et al, 2006).…”

Development of Non-peptidic Farnesyltransferase Inhibitors based on the Ca1a2of Ras-CaaX

“…Based on this result, we started designing non-peptidic compounds as the FTI since the peptide bonds and carboxyl group of 1 do not appear to play an important role for the binding activity other than conformational bias for proper placement of hydrophobic side chains. 6 We designed a non-peptidyl structure with amino-thiol group and hydrophobic group connected through a rigid spacer as shown in figure 1 based on the assumption that the peptide bonds adopt extended conformation for enzyme binding.…”

“…The binding activity of A 16 that can be viewed as ring constrained benzyl or reduced naphthyl group indicated that restriction of conformational freedom of the phenyl group of the A3 improved the binding activity by five fold while the reduction of an aromatic ring of A 14 to the cyclohexyl ring lowered the activity by ten fold. A polar group, especially the hydroxyl group attached to the naphthyl group interfered with the binding of the inhibitor (compounds A 6,17,19 ). All these results were in good agreement with the idea that these amide groups bind to the hydrophobic binding site created by the hole in the FTase and FPP bound to the enzyme.…”