Holder S, Zemskova, M. Zhang, C, Maryam, T. Bremer, R. Neidigh, JW, Lilly, MB. "Characterization of a Potent and Selective Small-Molecule Inhibitor of the PIM1 Kinase." Molecular Cancer Therapeutics. 6, 162 - 172 (2007) ( 8/2007 )
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 ELISAbased 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, ATPcompetitive inhibitor (IC50 = 0.34µM). Resolution of the crystal structure of PIM1 in complex with quercetagetin or three 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 to 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 = 5.5µM). RWPE2 cells treated with quercetagetin showed pronounced growth inhibition at inhibitor concentrations that blocked pim-1 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.