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 (IC(50), 0.34 micromol/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 (ED(50), 5.5 micromol/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.