title: Guiding farnesyltransferase inhibitors from an ECLiPS library to the catalytic zinc.
abstract: Farnesyltransferase inhibitors identified from an ECLiPS library were optimized using solution-phase synthesis. X-ray crystallography of inhibited complexes was used to identify substructures that coordinate to the active site zinc. The X-ray structures were ultimately used to guide the design of second-generation analogs with FTase IC(50)s of less than 1.0 nM.
authors.affiliation: Pharmacopeia Drug Discovery, PO Box 5350, Princeton, NJ 08543-5350, USA.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Huang
authors.forename: Tara M
authors.initials: TM
authors.lastname: Stauffer
authors.forename: Corey L
authors.initials: CL
authors.lastname: Strickland
authors.forename: John C
authors.initials: JC
authors.lastname: Reader
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.forename: Alan B
authors.initials: AB
authors.lastname: Cooper
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Doll
authors.forename: Ashit K
authors.initials: AK
authors.lastname: Ganguly
authors.forename: John J
authors.initials: JJ
authors.lastname: Baldwin
authors.forename: Laura L
authors.initials: LL
authors.lastname: Rokosz
mesh_terms: D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis; D020128:Inhibitory Concentration 50; D051379:Mice; D041681:NIH 3T3 Cells; D019151:Peptide Library; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D019151:Peptide Library; D051231:Farnesyltranstransferase; D015032:Zinc