Guiding farnesyltransferase inhibitors from an ECLiPS ® library to the catalytic zinc

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 3; pp. 507 - 511
• Main Authors: Huang, Chia-Yu, Stauffer, Tara M., Strickland, Corey L., Reader, John C., Huang, He, Li, Ge, Cooper, Alan B., Doll, Ronald J., Ganguly, Ashit K., Baldwin, John J., Rokosz, Laura L.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.02.2006; Elsevier
• Subjects: Animals; Anti-cancer; Antineoplastic agents; Binding Sites; Biological and medical sciences; Catalysis; Catalytic zinc; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Farnesyltransferase; Farnesyltranstransferase - antagonists & inhibitors; Farnesyltranstransferase - chemical synthesis; General aspects; Inhibitory Concentration 50; Medical sciences; Mice; NIH 3T3 Cells; Peptide Library; Pharmacology. Drug treatments; Rational drug design; Solution-phase synthesis; Structure-Activity Relationship; X-ray crystallography; Zinc - chemistry; Catalytic zinc; X-ray crystallography; Solution-phase synthesis; Anti-cancer; Farnesyltransferase; Rational drug design; Antineoplastic agent; Imidazole derivatives; Cyclohexane derivatives; Nitrogen heterocycle; Active site; Liquid phase; Farnesyl-diphosphate farnesyltransferase; Modeling; Pyridine derivatives; Structure activity relation; Chlorine Organic compounds; Chemical compound library; Six membered ring; Molecular model; Bromine Organic compounds; Aromatic compound; Chemical synthesis; Enzyme; Transferases; Enzyme inhibitor; Inhibitor enzyme complex; Tricyclic compound; X ray diffraction; In vitro
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.10.070

Compounds 8 and 41 are potent analogs of farnesyltransferase inhibitors that were identified from an ECLiPS ® library screen. X-ray crystallographic analyses of inhibited complexes show that the side-chain pyridyl of 8 and the imidazoyl of 41 coordinate to the active site zinc. 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 50s of less than 1.0 nM.