GGTase

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. 

Based on the CAAX motif, peptide analogues were designed in which peptide amide bonds are replaced by amine and ether groups [18]. In particular /I-turn mimetic 1 (Fig. 1) inhibits the FTase in vitro with an IC50 value of 1.8 nmol/1 and shows highly specific activity in comparison to inhibition of GGTase I. 

These chlorobenzocycloheptapyridines display pronounced selectivity for FTase over GGTase I. They show improved in vivo anti-tumor activity and pharmacokinetic profiles in mice when administered orally and inhibit H-Ras processing in Cos monkey kidney cells [43,44]. Extensive variation of the substituents on the piperidine moiety and the tricyclic ring system led to the devel-... 

Scheme 2 Intracellular processing of Rab proteins. Rab proteins form a complex with REP (Rab escort protein) that Is subsequently recognized by Rab GGTase-II and leads to geranylgeranylation of Rab.

In 2001 Alexandrov and coworkers developed a new two-plasmid expression system that allowed protein expression of GGTase-II at high levels and easy purification. Through this method the proteins were expressed as heterodimers with a-subunits bearing a cleavable 6His-glutathione 5-transferase (GST) tag. 

In addition to protein farnesylation, two other pathways exist for protein prenylation. As mentioned above, GGTase I also utilizes the C-terminal... 

AstraZeneca also entered a molecule (AZD-3409) (Fig. 4) into phase I/II studies [180]. AZD-3409 is a double prodrug inhibiting both FTase and GGTase I. AZD-3409 is converted in vivo into a prodrug, the main component in plasma of dosed animals, which is further metabolized in cells to the active drug. Recently published phase I data indicate that AZD-3409 was well... 

The prenyl transferases are a class of enzymes that is involved in post-translational modification of membrane-associated proteins. These enzymes catalyze the transfer of a farnesyl (FTase, EC 2.5.1.58, for structural information see References 55-65) or geranyl-geranyl group (GGTase I, EC 2.5.1.59 GGTase n, EC 2.5.1.60, for structural information... 

Fig. 6.4. Discovery of GGTase-I inhibitors with novel chemical scaffolds using a combination of QSAR modeling and virtual screening.

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