Benzodiazepine peptidomimetic inhibitors of farnesyltransferase

A structural survey of protein Zn 2+ binding geometries was instigated based upon the functional requirement of Ras farnesyltransferase for Zn 2+. The Cys-X-X-Cys motif found in Zn 2+-binding proteins such as aspartate transcarbamylase was used as a template to devise a bidentate-coordination model for Cys-A 1-A 2-X peptide inhibitors. Accordingly, replacement of the central dipeptide with the hydrophobic scaffold 3-amino-1-carboxymethyl-2,3-dihydro-5-phenyl-1 H-1,4-benzodiazepin-2-one (BZA) yielded a peptidomimetic inhibitor, Cys(BZA)Met, of moderate potency (IC 50 = 400 nM). N-Methylation of the cysteine amide improved potency almost 1000-fold (IC 50 = 0.3–1 nM). The increased affinity presumably correlates with a preferred conformation of the inhibitor which maximizes a hydrophobic interaction between the scaffold and the enzyme, and the proper presentation of cysteine and methionine to allow bidentate coordination at Zn 2+. These non-peptide inhibitors have been shown to block famesylation of the Ras protein in intact cells and provide lead compounds for the development of new cancer therapeutic agents. The synthesis of novel inhibitors of CAAX protein farnesyltransferase in which the central dipeptide (A 1A 2) has been replaced with 3-aminomethyl-1-carboxymehtyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiapezin-2-one (BZA) are described (IC 50 = 0.3 nM).