title: Synthesis, molecular modeling, and structure-activity relationship of benzophenone-based CAAX-peptidomimetic farnesyltransferase inhibitors.
abstract: Because of the involvement of farnesylated proteins in oncogenesis, inhibition of the protein-modifying enzyme farnesyltransferase is considered a major emerging strategy in cancer therapy. Here, we describe the structure-activity relationship of a novel class of CAAX-peptidomimetic farnesyltransferase inhibitors based on the benzophenone scaffold. 4'-Methyl, 4'-chloro, 4'-bromo, and 4'-nitrophenylacetic acid as substituents at the 2-amino group of the benzophenone core structure yield farnesyltransferase inhibitors active in the nanomolar range. Using diphenylacetic acid in this position further improves activity. SEAL superimposition of inhibitor 12a to the enzyme-bound conformation of a CAAX-peptide shows a markedly good resemblance of the molecular properties of the peptide. FlexX docking of 12a confirms the good fit of the molecule into the peptide binding site of farnesyltransferase. The novel benzophenone-based AAX-peptidomimetic substructure described here will be useful for the design of some novel types of farnesyltransferase inhibitors.
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Sakowski
authors.forename: M
authors.initials: M
authors.lastname: Böhm
authors.forename: I
authors.initials: I
authors.lastname: Sattler
authors.forename: H M
authors.initials: HM
authors.lastname: Dahse
authors.forename: M
authors.initials: M
authors.lastname: Schlitzer
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003545:Cysteine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001577:Benzophenones; D004791:Enzyme Inhibitors; C435189:N-(3-benzoyl-4-(2-(4-methylphenyl)acetylamino)phenyl)cysteinamide; D010446:Peptide Fragments; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D003545:Cysteine