Exploring Structure-Activity Relationships of Tricyclic Farnesyltransferase Inhibitors Using ECLiPS® Libraries

Author(s): Laura L. Rokosz, Chia-Yu Huang, John C. Reader, Tara M. Stauffer, Eileen C. Southwick, Ge Li, Daniel Chelsky, John J. Baldwin.

Journal Name: Combinatorial Chemistry & High Throughput Screening

Volume 9 , Issue 7 , 2006

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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.

Keywords: cancer, combinatorial chemistry, high throughput screening, ECLiPS, Farnesyltransferaser

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Article Details

VOLUME: 9
ISSUE: 7
Year: 2006
Page: [545 - 558]
Pages: 14
DOI: 10.2174/138620706777935379
Price: $58