2o64: Difference between revisions

Revision as of 19:15, 21 February 2008

Crystal structure of Pim1 with Quercetagetin

OverviewOverview

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.

About this StructureAbout this Structure

2O64 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.

ReferenceReference

Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase., Holder S, Zemskova M, Zhang C, Tabrizizad M, Bremer R, Neidigh JW, Lilly MB, Mol Cancer Ther. 2007 Jan;6(1):163-72. Epub 2007 Jan 11. PMID:17218638

Page seeded by OCA on Thu Feb 21 18:14:54 2008

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-[[Image:2o64.gif|left|200px]]<br />
+[[Image:2o64.gif|left|200px]]<br /><applet load="2o64" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2o64" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2o64, resolution 2.44&Aring;" />
 '''Crystal structure of Pim1 with Quercetagetin'''<br />
 ==Overview==
-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.
+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.
 ==About this Structure==
-O64 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with IMD and MYU as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2O64 OCA].
+O64 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=IMD:'>IMD</scene> and <scene name='pdbligand=MYU:'>MYU</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2O64 OCA].
 ==Reference==
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 [[Category: Bremer, R.]]
 [[Category: Holder, S.]]
-[[Category: Lilly, M.B.]]
+[[Category: Lilly, M B.]]
-[[Category: Neidigh, J.W.]]
+[[Category: Neidigh, J W.]]
 [[Category: Tabrizizad, M.]]
 [[Category: Zemskova, M.]]
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 [[Category: quercetagetin]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:07:02 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:14:54 2008''