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PDBsum entry 2o63
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References listed in PDB file
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Key reference
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Title
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Characterization of a potent and selective small-Molecule inhibitor of the pim1 kinase.
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Authors
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S.Holder,
M.Zemskova,
C.Zhang,
M.Tabrizizad,
R.Bremer,
J.W.Neidigh,
M.B.Lilly.
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Ref.
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Mol Cancer Ther, 2007,
6,
163-172.
[DOI no: ]
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PubMed id
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Abstract
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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.
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