Structure based design of benzophenone-based non-thiol farnesyltransferase inhibitors

Farnesyltransferase catalyzes the transfer of a farnesyl residue from farnesylpyrophosphate to the thiol of a cysteine side chain of proteins which carry at the C-terminus the so called CAAX-sequence. Although the exact cellular events affected by farnesyltransferase inhibiton remain to be determined, farnesyltransferase has become a major target in the development of potential anti-cancer drugs. Numerous farnesyltransferase inhibitors have been described from which the majority are CAAX-peptidomimetics possessing a free thiol group which coordinates the enzyme-bound zinc ion. The development of farnesyltransferase inhibitors is clearly directed towards the so-called non-thiol farnesyltransferase inhibitors because of adverse drug effects connected to free thiols. This review mainly deals with the efforts of the authers group towards the design of non-thiol-farnesyltransferase inhibitors. Our first step on the way to non-thiol farnesyltransferase inhibitors was the development of an CAAX-peptidomimetic based on a pharmacophore model. On the basis of this benzophenone core, bisubstrate analogues were developed as one class of non-thiol farnesyltransferase inhibitors. In most non-thiol farnesyltransferase inhibitors known in literature nitrogene containing heterocycles are used as cysteine replacements supposedly coordinating the enzyme bound zinc. However, we and others have shown that nitrogen heterocycles can be replaced by aryl residues lacking the ability to coordinate metal atoms, an observation which let to the postulation of two hitherto unknown aryl binding sites. Using flexible docking of model compounds and GRID analysis we were able to locate these postulated aryl binding sites. Subsequently, we used one of this aryl binding sites for the structure based design of highly active non-thiol farnesyltransferase inhibitors.