title: Farnesyl protein transferase inhibitors targeting the catalytic zinc for enhanced binding.
abstract: Successful efforts to make farnesyl transferase (FT) inhibitors with appropriately tethered ligands designed to interact with a catalytic zinc that exist in the enzyme have been realized. Thus, by introducing either a pyridylmethylamino or propylaminolimidazole amide moieties off the 2-position of the piperidine ring, FT inhibitors with activities in the picomolar range have been achieved as exemplified by compounds 12a and 12b. An X-ray structure of 11b bound to FT shows the enhanced activity is a result of interacting with the active-site zinc.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-3-3545, Kenilworth, NJ 07033, USA. george.njoroge@spcorp.com
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.forename: Paul
authors.initials: P
authors.lastname: Kirschmeier
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bishop
authors.forename: V
authors.initials: V
authors.lastname: Girijavallabhan
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D015032:Zinc / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D015032:Zinc