title: Design, synthesis, and characterization of peptide-based rab geranylgeranyl transferase inhibitors.
abstract: Rab geranylgeranyl transferase (RabGGTase) catalyzes the attachment of geranylgeranyl isoprenoids to Rab guanine triphosphatases, which are key regulators in vesicular transport. Because geranylgeranylation is required for proper function and overexpression of Rabs has been observed in various cancers, RabGGTase may be a target for novel therapeutics. The development of selective inhibitors is, however, difficult because two related enzymes involved in other cellular processes exist in eukaryotes and because RabGGTase recognizes protein substrates indirectly, resulting in relaxed specificity. We report the synthesis of a peptidic library based on the farnesyl transferase inhibitor pepticinnamin E. Of 469 compounds investigated, several were identified as selective for RabGGTase with low micromolar IC(50) values. The compounds were not generally cytotoxic and inhibited Rab isoprenylation in COS-7 cells. Crystal structure analysis revealed that selective inhibitors interact with a tunnel unique to RabGGTase, implying that this structural motif is an attractive target for improved RabGGTase inhibitors.
authors.affiliation: Department of Chemical Biology, Biochemistry, Max Planck Institute of Molecular Physiology,Otto-Hahn-Strassse 11, 44227 Dortmund, Germany.
authors.forename: Kui-Thong
authors.initials: KT
authors.lastname: Tan
authors.forename: Ester
authors.initials: E
authors.lastname: Guiu-Rozas
authors.forename: Robin S
authors.initials: RS
authors.lastname: Bon
authors.forename: Zhong
authors.initials: Z
authors.lastname: Guo
authors.forename: Christine
authors.initials: C
authors.lastname: Delon
authors.forename: Stefan
authors.initials: S
authors.lastname: Wetzel
authors.forename: Sabine
authors.initials: S
authors.lastname: Arndt
authors.forename: Kirill
authors.initials: K
authors.lastname: Alexandrov
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.forename: Roger S
authors.initials: RS
authors.lastname: Goody
authors.forename: Yao-Wen
authors.initials: YW
authors.lastname: Wu
authors.forename: Wulf
authors.initials: W
authors.lastname: Blankenfeldt
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D019556:COS Cells; D020134:Catalytic Domain; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019151:Peptide Library; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019151:Peptide Library; C080552:pepticinnamin E; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase; C064911:p21(ras) farnesyl-protein transferase