From peptide libraries to optimized nonpeptide ligands in the search for S‐farnesyltransferase inhibitors

Abstract: A complete 331 776‐member library of tetrapeptides made of 24 amino acid building blocks was synthesized robotically on solid phase and subjected to a deconvolution based on the inhibitory potency of the sublibraries in a HPLC assay of the S‐farnesyltransferase activity in vitro. One of the non‐natural peptide and noncysteine‐containing leads Nip‐Trp‐Phe‐His (Nip = p‐nitrophenyl‐l ‐alanine) was optimized chemically to give a proteolytically stable pseudopeptide with a 200‐fold potency compared with the original lead. The final compound was converted to the C‐terminal ethyl ester: p‐F‐C₆H₄‐CO(CH₂)₂‐CO‐Bta‐d ‐PheψCH2NH]His‐OEt (Bta = benzothienyl‐l ‐alanine) and shown to behave as a prodrug which was hydrolyzed back to the C‐terminal acid following cell penetration. The method confirmed that several structurally original leads can be discovered in large libraries when deconvolution relies upon a highly specific assay and that these leads can be optimized by chemical modification to impart the final compound the desired pharmacological and pharmacokinetic properties.