title: Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase.
abstract: A series of imidazole-containing peptidomimetic PFTase inhibitors and their co-crystal structures bound to PFTase and FPP are reported. The structures reveal that the peptidomimetics adopt a similar conformation to that of the extended CVIM tetrapeptide, with the imidazole group coordinating to the catalytic zinc ion. Both mono- and bis-imidazole-containing derivatives, 13 and 16, showed remarkably high enzyme inhibition activity against PFTase in vitro with IC50 values of 0.86 and 1.7 nM, respectively. The peptidomimetics were also highly selective for PFTase over PGGTase-I both in vitro and in intact cells. In addition, peptidomimetics and were found to suppress tumor growth in nude mouse xenograft models with no gross toxicity at a daily dose of 25 mg kg(-1).
authors.affiliation: Department of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Ohkanda
authors.forename: Corey L
authors.initials: CL
authors.lastname: Strickland
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: Dora
authors.initials: D
authors.lastname: Carrico
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Lockman
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Bucher
authors.forename: Jiazhi
authors.initials: J
authors.lastname: Sun
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qian
authors.forename: David
authors.initials: D
authors.lastname: Knowles
authors.forename: Erin E
authors.initials: EE
authors.lastname: Pusateri
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D010455:Peptides; C029899:imidazole; D051231:Farnesyltranstransferase