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Journal of Biomolecular Screening
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A Cell-Based Radioligand Binding Assay for Farnesyl: Protein Transferase Inhibitors

Robert B. Lobell

Department of Cancer Research, Merck Research Laboratories, West Point, PA rob_lobell{at}merck.com

Joseph P. Davide

Department of Cancer Research, Merck Research Laboratories, West Point, PA

Nancy E. Kohl

Department of Cancer Research, Merck Research Laboratories, West Point, PA

H. Donald Burns

Department Imaging Research, Merck Research Laboratories, West Point, PA

Wai-Si Eng

Department Imaging Research, Merck Research Laboratories, West Point, PA

Raymond E. Gibson

Department Imaging Research, Merck Research Laboratories, West Point, PA

Farnesyl:protein transferase (FPTase) catalyzes the covalent addition of the isoprenyl moiety of farnesylpyrophosphate to the C-terminus of the Ras oncoprotein and other cellular proteins. Inhibitors of FPTase (FTIs) have been developed as potential anticancer agents, and several compounds have been evaluated in clinical trials. To facilitate the identification of cell-active FTIs with high potency, the authors developed a method that uses a radiolabeled FTI that serves as a ligand in competitive displacement assays. Using high-affinity [3H]-labeled or [125I]-labeled FTI radioligands, they show that specific binding to FPTase can be detected in intact cells. Binding of these labeled FTI radioligands can be competed with a variety of structurally diverse FTIs, and the authors show that inhibition of FTI radioligand binding correlates well with inhibition of FPTase substrate prenylation in cells. This method provides a rapid and quantitative means of assessing FTI potency in cells and is useful for guiding the discovery of potent, novel inhibitors of FPTase. Similar methods could be employed in the optimization of inhibitors for other intracellular drug targets.

Key Words: radioligand binding assays • CRAFTI • FPTase • cancer • cell culture models • farnesyltransferase inhibitors • P-glycoprotein

Journal of Biomolecular Screening, Vol. 8, No. 4, 430-438 (2003)
DOI: 10.1177/1087057103256153
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