Farnesyl transferase inhibitors

Farnesyl transferase from rat cells is a heterodimer consisting of a 48 kD u-snbnnit and a 46 kD /3-snbnnit. In the structure shown here, helices 2 to 15 of the u-snbnnit are folded into seven short coiled coils that together form a crescent-shaped envelope partially surrounding the /3-snbnnit. Twelve helices of the /3-snl> nnit form a novel barrel motif that creates the active site of the enzyme. Farnesyl transferase inhibitors, one of which is shown here, are potent suppressors of tumor growth in mice, but their value in humans has not been established. 

The structure of 1-739,749, a farnesyl transferase inhibitor that is a potent tumor growth suppressor. 

Rheb Elevated in many tumor cells, Rheb may be the critical target by which farnesyl transferase inhibitors inhibit tumor growth... 

The protein Ras, an important intracellular signal transducer, is crucially involved in the development of tumor growth. The farnesylation of Ras, catalyzed by the enzyme Ras-farnesyl-transferase, is essential to its proper functioning in the normal and in the transformed state. Therefore, the inhibition of Ras lipidation has become a promising target for the development of new classes of anti-tumor agents. This review focuses on the different classes of Ras-farnesyl-transferase inhibitors and compares their biological properties and modes of action in vitro as well as in vivo. 

Scheme 2.45 Synthesis of potential enzyme farnesyl transferase inhibitors.

Perola, E., Xu, K., Kollmeyer, T.M., Kaufmann, S.H., and Prendergast, F.G. Successful virtual screening of a chemical database for farnesyl-transferase inhibitor leads./. Med. 

Keywords Farnesyl transferase inhibitor Protein prenylation Ras protein ... 

Although this second route is a type a ring construction, it is included here for convenience and comparison with the type b approach. The benzazepinone 142 was converted into the N-substituted derivatives 143, which were potent and specific farnesyl transferase inhibitors (Scheme 19) <2004BML767>. 

FARNESYL TRANSFERASE INHIBITORS DESIGN OF A NEW CLASS OF CANCER CHEMOTHERAPEUTIC AGENTS... 

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