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Research Articles: Therapeutics, Targets, and Development

Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase

¹ Center for Molecular Biology and Gene Therapy, Departments of ² Biochemistry and Microbiology and ³ Medicine, Loma Linda University School of Medicine, Loma Linda, California; and ⁴ Plexxikon, Inc., Berkeley, California

Requests for reprints: Michael B. Lilly, Center for Molecular Biology and Gene Therapy, Loma Linda University School of Medicine, 11234 Anderson Street, Loma Linda, CA 92354. Phone: 909-558-8777; Fax: 909-558-0177. E-mail: mlilly{at}llu.edu

Abstract

The pim-1 kinase is a true oncogene that has been implicated in the development of leukemias, lymphomas, and prostate cancer, and is the target of drug development programs. We have used experimental approaches to identify a selective, cell-permeable, small-molecule inhibitor of the pim-1 kinase to foster basic and translational studies of the enzyme. We used an ELISA-based kinase assay to screen a diversity library of potential kinase inhibitors. The flavonol quercetagetin (3,3',4',5,6,7-hydroxyflavone) was identified as a moderately potent, ATP-competitive inhibitor (IC₅₀, 0.34 µmol/L). Resolution of the crystal structure of PIM1 in complex with quercetagetin or two other flavonoids revealed a spectrum of binding poses and hydrogen-bonding patterns in spite of strong similarity of the ligands. Quercetagetin was a highly selective inhibitor of PIM1 compared with PIM2 and seven other serine-threonine kinases. Quercetagetin was able to inhibit PIM1 activity in intact RWPE2 prostate cancer cells in a dose-dependent manner (ED₅₀, 5.5 µmol/L). RWPE2 cells treated with quercetagetin showed pronounced growth inhibition at inhibitor concentrations that blocked PIM1 kinase activity. Furthermore, the ability of quercetagetin to inhibit the growth of other prostate epithelial cell lines varied in proportion to their levels of PIM1 protein. Quercetagetin can function as a moderately potent and selective, cell-permeable inhibitor of the pim-1 kinase, and may be useful for proof-of-concept studies to support the development of clinically useful PIM1 inhibitors. [Mol Cancer Ther 2007;6(1):163–72]

Grant support: Department of Defense, Congressionally Directed Medical Research Program, Award W81XWH-04-1-0887.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 7/10/06; revised 10/10/06; accepted 11/17/06.

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