CAAX peptidomimetics

V. Design of CaaX Peptidomimetics as PTIs and Identification of PTIs from High-Throughput Screens (HTS)... 

Compound 3 is a nonpeptidomimetic inhibitor, whereas all other PTTs are either CaaX peptidomimetics or inhibitors from high-throughput screening campaigns. 

Through systematic modification of the imidazole-appended 2-phenyl-aminobenzoate peptidomimetic scaffold (e.g., FTI-2148) a group at Abbott Pharmaceuticals have identified an expanded series of inhibitors that lack either the C-terminal Met carboxylate (as in compounds 14-23 of Ref. [55]) or the imidazole group (as in ABT-839) [56,70,71]. This latter compound became a clinical candidate and demonstrates that coordination to the zinc ion is not a prerequisite for potent inhibitors of FT. In place of metal-ligand (imidazole, thiol, etc.) coordination, ABT-839 exploits hydrophobic contact from the cyclohexylethyl and -butyl groups to the protein-binding pocket. For the structures of other CaaX peptidomimetics, please refer to Table 6.1. 

Scheme 4. Syntheses of an alkene moiety containing CAAX peptidomimetic.

Recently, crystal structures of famesyl-transferase complexed with a farnesyl group donor and the native substrate or a type I peptidomimetic show the structural basis for inhibition of this enzyme. The X-ray data show that the CAAX motif adopts an extended conformation rather than a /3-tum, which is the conformation observed by transferred nuclear... 

Peptoids [22] form a particular promising class of oligomeric peptidomimetics, which consists of A-substituted-glycine derivatives. Thus, the concepts to translate a particular peptide sequence, in this case CAAX to a corresponding peptoid sequence is a perfectly suitable approach to obtain potential famesyl inhibitors. This approach was adopted by... 

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