Protein farnesyltransferase inhibitor

Takada, Y., Khuri, F.R., and Aggarwal, B.B. (2004). Protein farnesyltransferase inhibitor (SCH 66336) abolishes NF-kB activation induced by various carcinogens and inflammatory stimuli leading to suppression of NF-KB-regulated gene expression and up-regulation of apoptosis. J Biol Chem 279 26287-26299. 

Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria. J Lipid Res 51 400-405. 

Hucke O, Gelb MH, Verlinde CL et al. The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease. J Med Chem 2005 48 5415-18. 

Bendale P, Olepu S, Suryadevara PK, Bulbule V, Rivas K, NaUan L, Smart B, Yokoyama K, Ankala S, Pendyala PR, Floyd D, Lombardo LJ, Williams DK, Buckner FS, Chakrabarti D, Verhnde CLMJ, Van Voorhis WC, Gelb MH (2007) Second generation tetrahydroquinoUne-based protein farnesyltransferase inhibitors as antimalarials. J Med Chem 50 4585 605... 

Patnaik A, Rowinsky EK (2001) Early clinical experience with farnesyl protein transferase inhibitors. In Sebti SM, Hamilton AD (eds) Farnesyltransferase inhibitors in cancer therapy. Humana, Totowa, NJ, pp 233-249... 

Protein farnesyltransferase (PFT) is responsible for farnesylation of cellular proteins, and PFT inhibitors have recently been developed for treatment of diseases involving farnesylated proteins. 

Overhand, M., et al. (1998). Inhibitors of protein farnesyltransferase and protein geranyl-geranyl transferase I Synthesis of homologous diphosphonate analogues of isoprenylated pyrophosphate. Bioorg Chem 26 269-282. 

Curtin, M.L., Florjancic, A.S., Cohen, J., Gu, W.Z., Frost, D.J., Muchmore, S.W., and Sham, H.L. (2003). Novel and selective imidazole-containing biphenyl inhibitors of protein farnesyltransferase. Bioorg Med Chem Lett 13 1367-1371. 

A series of novel 1,6-naphtyridine derivatives were prepared as potential inhibitors of human topoisomerase I (2003JMC2254), farnesyltransferase inhibitors (2003USP2003199544), p38 mitogen-activated protein kinase inhibitors (2003MI7), SYK kinase inhibitors (2003PIAW02003057695) and spleen tyrosine kinase inhibitors (2003MI8). 

Protein farnesylation, catalyzed by protein farnesyltransferase, plays important roles in the membrane association and protein-protein interaction of a number of eukaryotic proteins. The enzyme transfers a 15-carbon farnesyl moiety from famesyl diphosphate (FPP) to the sulfhydryl group of cysteine. The activity of the enzyme was measured by CE with LIE detection, which is a powerfiil alternative to classical methods involving radiolabeled FPP." LIE detection was performed with an argon ion laser (excitation, 488 nm/emission, 520 nm). A fluorescently labeled pentapeptide that was used as substrate was clearly separated from its farnesylated form under the four CE buffer conditions investigated (e.g., 25 mM borax, 25 mM SDS, pH 9.3, uncoated capillary). The method will be of great value in studies of inhibitors of protein farnesyltransferase in vitro. 

Thutewohl, M. et al., Identifieation of mono- and bisubstrate inhibitors of protein farnesyltransferase and inducers of apoptosis fiom a pepticinnamin E library, Bioorg. Med Chem., 11, 2617, 2003. Suda, A. et al.. Combinatorial synthesis of nikkomydn analogs on solid-support. Heterocycles, 55 1023, 2001. 

This subsection is a continuation of the review of biological aspects of synthesized molecules, which have been mentioned in the previous subsections devoted to synthesis and reactions. Synthesis and biochemical evaluation of 3,7-disubstituted farnesyl diphosphate (FPP) analogues (67) have been described by Gibbs and co-workers as both potent inhibitors of protein-farnesyltransferase (FTase) and efficient, alternative substrates for the FTase. ... 

Tamanoi, R, Gau, C.L., Jiang, C., Edamatsu, H., Kato-Stankiewicz, J. (2001). Protein tamesylation in mammalian cells effects of farnesyltransferase inhibitors on cancer cells. Cell Mol. Life Sci. 5S(11), 1636-1649. 

Farnesyltransferase is a heterodimeric protein composed of an a- and a /1-sub-unit, and zinc and magnesium ions are required for its activity [7,8]. A closely related heterodimeric enzyme is geranylgeranyltransferase I (GGTase I). It also recognizes proteins with a CAAX-box when X is leucine. Both enzymes share the same a-subunit and the requirement for Zn2+ and Mg2+ but the /1-subunits are different. The similarity of these enzymes highlights the importance of selectivity of farnesyltransferase (FT)-inhibitors. 

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... 

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