title: Design, synthesis, and evaluation of potent and selective benzoyleneurea-based inhibitors of protein geranylgeranyltransferase-I.
abstract: A series of novel protein geranylgeranyltransferase-I (PGGTase-I) inhibitors based on a benzoyleneurea scaffold has been synthesized. Using a benzoyleneurea scaffold as a mimetic for the central dipeptide (AA), we have developed CAAX peptidomimetic inhibitors that selectively block the activity of PGGTase-I over the closely related enzyme protein farnesyltransferase. In this new class of PGGTase-I inhibitors, compound (6c) with X=L-phenylalanine, displayed the highest inhibition activity against PGGTase-I with an IC50 value of 170 nM. The inhibitors described in this study represent novel and promising leads for the development of potent and selective inhibitors of mammalian PGGTase-I for potential application as antitumor agents.
authors.affiliation: Department of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520, USA.
authors.forename: Dora
authors.initials: D
authors.lastname: Carrico
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Bucher
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry / Q000379:methods; D008958:Models, Molecular; D015394:Molecular Structure; D014508:Urea / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014508:Urea; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I