Farnesyl inhibitors

Toxicity and effectivity studies have often been performed in rodent fibroblast cells containing oncogenic H-Ras. However, prenylation of K-Ras B and N-Ras are not as effectively blocked by the farnesyltransferase inhibitors as H-Ras [48] (see below). Thus normal cells may be less sensitive to these drugs because they express K-Ras 4B and N-Ras. In this context it should be noted that H-Ras mutations are relatively uncommon in human tumors [49]. Rather, the K-Ras gene is the most frequently mutated in solid human cancers, whereas N-Ras is prevalent in leukemias. Thus the preclinical evaluation of the farnesylation inhibitors has yet to be critically re-evaluated for trials in humans. 

Introduction Cyclooxygenase-2 Antiangiogenesis Agents Signal Transduction Inhibitors Ras Farnesylation Inhibitors Cell Cycle Inhibitors Promotors of Apoptosis Conclusions References... 

Farnesyl transferase from rat cells is a heterodimer consisting of a 48 kD u-snbnnit and a 46 kD /3-snbnnit. In the structure shown here, helices 2 to 15 of the u-snbnnit are folded into seven short coiled coils that together form a crescent-shaped envelope partially surrounding the /3-snbnnit. Twelve helices of the /3-snl> nnit form a novel barrel motif that creates the active site of the enzyme. Farnesyl transferase inhibitors, one of which is shown here, are potent suppressors of tumor growth in mice, but their value in humans has not been established. 

The structure of 1-739,749, a farnesyl transferase inhibitor that is a potent tumor growth suppressor. 

Rheb Elevated in many tumor cells, Rheb may be the critical target by which farnesyl transferase inhibitors inhibit tumor growth... 

Farnesyl protein inhibitor 2 Flavones 254 Fluorous phases 112 Fluorous Ugi reactions 115 Functional group transformations 25... 

Fig. 1 Heterocycles bearing a 2-pyridone moiety with wide range of medicinal applications. Amrinone WIN 40680 1 is a cardiotonic agent for the treatment of heart failure. ZAR-NESTRA 2 is a selective farnesyl protein inhibitor and NP048 3 is a pilicide with novel antibacterial properties. The 2-pyridones 4, 5 and 6 are schematic representations of the three categories of 2-pyridones that wiU be covered in this chapter i.e., substituted 2-pyridones 4, 2-quinolones 5 and other ring-fused 2-pyridones 6...

Caliendo G et al. (1999) Synthesis and biological activity of pseudopeptide inhibitors of Ras farnesyl transferase containing unconventional amino acids. Farmaco 54(11-12) 785-790... 

The protein Ras, an important intracellular signal transducer, is crucially involved in the development of tumor growth. The farnesylation of Ras, catalyzed by the enzyme Ras-farnesyl-transferase, is essential to its proper functioning in the normal and in the transformed state. Therefore, the inhibition of Ras lipidation has become a promising target for the development of new classes of anti-tumor agents. This review focuses on the different classes of Ras-farnesyl-transferase inhibitors and compares their biological properties and modes of action in vitro as well as in vivo. 

However, 2 also affected the regulation of actin stress fiber formation [19]. Rho proteins are involved in the regulation of various cytoskeletal structures, and RhoB is believed to be one of the prime targets of FTase inhibitors. Rho B is apparently both geranylgeranylated and farnesylated [20, 21]. If cells were treated with 2, vesicular localization of Rho B was inhibited. Thus 2 may also inhibit the farnesylation of Rho B, thereby interfering with actin stress fiber formation [22]. 

Further modifications of the CAAX tetrapeptide structure led to inhibitor 3 which blocked H-Ras farnesylation with an IC50 of 11 nmol/1 [23]. Tumor cell lines expressing mutant H- and N-Ras were most sensitive against this compound that inhibits tumor growth of EJ-1 human bladder carcinomas by about... 

The central unit of these peptidomimetics imitates a /1-turn and brings the NH2-terminus of the cysteine analogue and the CO OH terminus of the methionine in spatial proximity these can then complex the Zn2+ ion which is essential for activity of the FTase [26]. The free acid 7 inhibits the enzyme with an IC50 value of 1 nmol/1, whilst in intact cells the methyl ester 8, despite its weaker in vitro activity, is significantly more potent because it can penetrate the plasma membrane better due to its lower polarity. This property can be used to convert the morphology of H-Ras-transformed cells back to the normal form and to inhibit growth of these cells, whereas the substance shows no effect on Src-transformed and untransformed rat fibroblasts. The inhibitor therefore acts selectively on transformed cells and does not influence growth of normal cells. This result is noteworthy because farnesylation of the wild type H-Ras protein... 

The design of FTase inhibitors based on the structure of farnesyl pyrophosphate has been pursued with less intensity due to the possible nonselective effects of competing with other enzymes such as squalene synthetase that also accept farnesylpyrophosphate as substrate [3,4,9,10-12]. 

However, bisubstrate inhibitors incorporating a farnesyl- and a CAAX mimetic are very promising since one can expect that they display enhanced... 

Although FTase inhibitors influence the farnesylation of Ras they are likely to interfere with the posttranslational modifications of other CAAX-containing proteins as well. Apart from the approximately 20 farnesylated proteins that are known today, farnesylation is also required for normal Ras function which in turn is critical for normal cell viability. For these reasons farnesyltransferase... 

Synthesis of Characteristic Lipopeptides of the Human N-Ras Protein and Their Evaluation as Possible Inhibitors of Protein Farnesyl Transferase, P. Stober, M. Schelhaas, E. Nagele, P. Hagenbuch, J. R etey, H. Waldmann, Bioorg. Med. Chem 1997, 5,75-83. 

Inhibitors of farnesyl protein transferase 2003BM L4365... 

Protein prenylation leads to an increased hydrophobicity of proteins, typically resulting in an increased affinity for membranes. In 2004 studies on the cellular location of prenylated RhoB proteins showed that RhoB can undergo farnesylation (RhoB-F) as well as geranylgeranylation (RhoB-GG). With the aid of specific prenyl transferase inhibitors, it was revealed that RhoB-GG is localized to multivesicular late endosomes. 

Sn2 substitution using organocopper reagents is an efficient method for the synthesis of 3-substituted olefins. In the synthesis of farnesyl diphosphate analogues (43, 45) as potential inhibitors of the enzyme protein-farnesyl transferase, for example, organocopper methodology was compared with the Stifle reaction [33] and the Suzuki reaction [34], frequently used in the coupling of vinyl triflates with... 

Scheme 2.45 Synthesis of potential enzyme farnesyl transferase inhibitors.

Perola, E., Xu, K., Kollmeyer, T.M., Kaufmann, S.H., and Prendergast, F.G. Successful virtual screening of a chemical database for farnesyl-transferase inhibitor leads./. Med. 

---