Famesyl transferase

Nagasu T, Yoshimatsu K, Rowell C, et al. Inhibition of human tumor xenograft growth by treatment with the famesyl transferase inhibitor B956. Cancer Res 1995 55 5310-5314. 

Another approach to the management of IM resistance is to combine agents that are individually active against CML but have differing mechanisms of action that may allow either additive or synergistic effects in a non-cross-resistant marmer. This approach has been extensively studied in the literature and will not be reviewed in detail here. An excellent discussion of combination therapy is foimd in the reviews by Hochhaus and La Rosee (52,85). Some combination approaches have utilized famesyl transferase inhibition such as lonafamib in combination with IM, inhibitors of the mammalian target of rapamycin (mTOR) in combination with IM and combining mycophenolic acid, an inhibitor of the JAK-STAT pathway. 

An example of the signal-transduction protein-targeted inhibitor design which illustrates both peptide scaffold- and nonpeptide template-based approaches is that for the Ras famesyl transferase inhibitor discovery. Such compounds show potential as new therapeutic agents for Ras-related carcinogenesis [81]. Substrate sequences for famesyl transferase have the consensus Cy s-A A, - A A2-Met motif (AA refers to Val or lie). Both substrate-based... 

Peptide scaffold- and nonpeptide template-based design strategies famesyl transferase... 

Gamer, R. C., Goris, I., Laenen, A. A., Vanhoutte, E., Meuldermans, W., Gregory, S., Gamer, J. V., Leong, D., Whattam, M., Calam, A., and Snel, C. A. (2002). Evaluation of accelerator mass spectrometry in a human mass balance and pharmacokinetic study—Experience with 14C-labeled (R)-6-[amino(4-chlorophenyl)(l-methyl-l //-imidazol-5-yl)methyl -4-(3-chlorophenyl)- l-methyl-2(17/ i-quinolinone (R115777), a famesyl transferase inhibitor. Drug Metab. Dispos. 30 823-830. 

VIII. Biological Consequences of Famesyl Transferase Inhibition. 306... 

Addition of the terpene, famesol, to cysteine residues near the end of protein chains is a cmcial process for transporting some proteins to the intended membrane compartment. This process thus plays an important role in cell proliferation. Inhibitors of the enzyme that catalyzes farnesyla-tion, famesyl transferase, provide yet one more mechanism for interrupting the multiplication of malignant cells. One of several synthesis of this agent... 

Parallel liquid synthesis has been applied to the synthesis of a range of N,N -disubstituted 3-aminoazepin-2-ones 7 (e.g. R = w-BrC6H4) starting from 6. These compounds were required for SAR studies as specific famesyl transferase inhibitors <03BMC3193>. 

Several enzyme classes have been targeted using the positional scanning approach, such as famesyl transferase (74) and a-glucosidase (75) the latter establishes that the screening of peptide libraries is not limited to enzymes that transform peptides. 

JH, Jarman M. Solid-phase synthesis of novel inhibitors of famesyl transferase. Bioorg. Med. Chem. Lett. 1999 9 623-626. 

Recently, crystal structures of famesyl-transferase complexed with a farnesyl group donor and the native substrate or a type I peptidomimetic show the structural basis for inhibition of this enzyme. The X-ray data show that the CAAX motif adopts an extended conformation rather than a /3-tum, which is the conformation observed by transferred nuclear... 

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

Roy R, Knowles R (1995) Differential inhibition by allylsulfide of nitrification and methane oxidation in freshwater sediment. Appl Environ Microbiol 61 4278 1283 Saiki K, Mogi T, Anraku Y (1992) Heme O biosynthesis in Escherichia coli the cyoE gene in the cytochrome bo operon encodes a protoheme IX famesyl transferase. Biochem Biophys Res Commun 189 1491-1497... 

HTS for nonpeptide inhibitors of famesyl transferase led to the potent inhibitor SCH 66701 (23.50, Fig. 23.12) which was crystallized within the enzyme active site. This completely nonpeptidic inhibitor is reminiscent of the classical tricyclic CNS agents and contains one of the classical pharmacophores resistant to hydrophobic collapse it contains only two readily rotatable bonds. This inhibitor shows that potency can be achieved even without the essential cysteine or sulfhydryl mimic. More recently, a series of macrocyclic 3-aminopyrrolidinone famesyltrans-ferase inhibitors, (e.g. 23.51), has shown that cyclization provides enhanced plasma half-life, attenuates metabolic... 

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