Protein farnesyl transferase

Inhibitors of farnesyl protein transferase 2003BM L4365... 

Angibaud et al. carried out thorough studies on the farnesyl protein transferase inhibitory activity of substituted azoloquinolines <2003BML4365>. These authors found that some tetrazolo[l,5-a]quinolines 161 (Scheme 38) are promising agents for oral in vivo inhibition. 

Kaminski, J.J., Rane, D.F., Snow, M.E., Weber, L, and Rothofsky, M.L Identification of novel farnesyl protein transferase inhibitors using three-dimensional database searching methods./. Med. Chem. 1997, 40, 4103-4112. 

Horvath D. (2001b) ComPharm—Automated comparative analysis of phar-macophoric patterns and derived QSAR approaches, novel tools in high throughput drug discovery. A proof-of-concept study applied to farnesyl protein transferase inhibitor design. In M Diudea (ed), QSPR/QSAR Studies by Molecular Descriptors, pp. 395-439, Nova Science Publishers, New York, USA. 

Abstract Over a decade has passed since the first report describing farnesyl protein transferase (FTase) and tetrapeptide inhibitors triggered a search for small-molecule inhibitors that could be developed as oral therapeutics. There are now several farnesyl protein inhibitors (FTIs) in various phases of clinical development and at least two compounds have entered phase III. The published data suggest some disappointing activity in the major solid tumors, with more promising activities emerging from studies of hemato-... 

Fig. 2 Schematic representation of the farnesyl protein transferase (FTase) reaction...

Fig. 4 CAAX competitive heterocyclic farnesyl protein transferase inhibitors. The inhibitors shown in the first row are reported to be in phase I, II, or III clinical development...

Fig. 6 Inhibitors of farnesyl protein transferase, which are competitive for farnesyl pyrophosphate binding...

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... 

End DW, Mevellec L, Angibaud P (2007) Farnesyl Protein Transferase Inhibitors Medicinal Chemistry, Molecular Mechanisms, and Progress in the Clinic. 1 115-150... 

Famesylation of the Ras protein occurs at the C-terminal CAAX sequence (A aliphatic amino acid, X Ser or Thr). The famesyl residue is attached, with the help of a farnesyl protein transferase, via a thioether bond to the Cys residue of the CAAX sequence. Next, the last three amino acids are cleaved off by proteases and the carboxyl group of the C-terminal cysteine residue undergoes a methylesterification (Fig. 9.6). In addition, the Ras proteins have a palmitinic acid anchor at different Cys residues in the vicinity of the C terminus. The membrane localization of the Ki-Ras protein is also supported by a polybasic sequence close to the C terminus (see 3.7 and Fig. 3.12). 

Amide and cyanoguanidine derivatives 265 and 266 containing a 5,ll-dihydro[l]benzothiepino[4,3-A pyridine ring system were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase <1998BML2521>. 

Chen X, Hasuma T, Yano Y, Yoshimata T, Morishima Y, Wang Y, Otani S. 1997. Inhibition of farnesyl protein transferase by monoterpene, curcumin derivatives and gallotannin. Anticancer Res 17 2555-2564. 

S Omura, D Van der Pyl, J Inokoshi, Y Takahashi, H Takeshima. Pepticinnamins, new farnesyl-protein transferase inhibitors produced by an actinomycete. I. Producing strain, fermentation, isolation and biological activity. J Antibiot 46 222-228, 1993. 

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