Farnesylated proteins

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...

Figure 17.21 An azido-farnesyl diphosphate derivative can be added to cells to obtain farnesylated proteins containing terminal azide groups that can be targeted in a Staudinger ligation reaction. Biotinylation of these post-translationally modified proteins can be done in vivo using a biotin-phosphine derivative.

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... 

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. 

Studying the sequences of farnesylated proteins indicated that all lipidated proteins bear a cysteine residue near the C-terminus revealing the CAAX-motif, where C is a cysteine, A stands for an aliphatic amino acid, and X can be any amino acid. Database searches resulted in more prenylated proteins, all bearing the CAAX-motif, in systems from lower eukaryotes to mammals. A closer look at the mature proteins revealed that prenylation was only the first step of processing of the CAAX-motif-encoded proteins. After transfer of the isoprene unit, the last three amino acids are cleaved proteolytically by an endoprotease and the C-terminal cysteine is carboxymethylated by a methyltransferase. ... 

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... 

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