title: Exploring structure-activity relationships of tricyclic farnesyltransferase inhibitors using ECLiPS libraries.
abstract: The development of structure-activity relationships (SARs) relating to the function of a biological protein is often a long and protracted undertaking when using an iterative medicinal chemistry approach. High throughput screening of ECLiPS (Encoded Combinatorial Libraries on Polymeric Support) libraries can be used to simplify this process. In this paper, we illustrate how a large ECLiPS library of 26,908 compounds, based on a tricyclic core structure, was used to define a multitude of SARs for the oncogenic target, farnesyltransferase (FTase). This library, FT-2, was prepared using a split-and-pool approach in which small molecules are constructed on resin that contains tag/linker constructs to track the synthetic process [1-5] Highly defined SARs were produced from this screen that enhanced our understanding of FTase binding site interactions. The pivotal compounds culled from this library were potent in both cell-free and cell-based FTase assays, selective over the closely related enzyme, geranylgeranyltransferase I (GGTase I), and inhibited the adherent-independent growth of a transformed cell line.
authors.affiliation: Pharmacopeia Drug Discovery, Inc., P.O. Box 5350, Princeton, New Jersey 08543, USA. rock@pharmacop.com
authors.forename: Laura L
authors.initials: LL
authors.lastname: Rokosz
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Huang
authors.forename: John C
authors.initials: JC
authors.lastname: Reader
authors.forename: Tara M
authors.initials: TM
authors.lastname: Stauffer
authors.forename: Eileen C
authors.initials: EC
authors.lastname: Southwick
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Chelsky
authors.forename: John J
authors.initials: JJ
authors.lastname: Baldwin
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D001665:Binding Sites; D001681:Biological Assay; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase