2O3P

Crystal structure of Pim1 with Quercetin

Summary for 2O3P

• Entry DOI: 10.2210/pdb2o3p/pdb
• Related: 2O63 2O64 2O65
• Descriptor: Proto-oncogene serine/threonine-protein kinase Pim-1, IMIDAZOLE, 3,5,7,3',4'-PENTAHYDROXYFLAVONE, ... (4 entities in total)
• Functional Keywords: pim1, quercetin, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• Total number of polymer chains: 1
• Total formula weight: 34272.73

Authors

Holder, S.,Zemskova, M.,Zhang, C.,Tabrizizad, M.,Bremer, R.,Neidigh, J.W.,Lilly, M.B. (deposition date: 2006-12-01, release date: 2007-02-13, Last modification date: 2023-12-27)

Primary citation

Holder, S.,Zemskova, M.,Zhang, C.,Tabrizizad, M.,Bremer, R.,Neidigh, J.W.,Lilly, M.B.
Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase.
Mol.Cancer Ther., 6:163-172, 2007

PubMed 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 (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.

PubMed: 17218638
DOI: 10.1158/1535-7163.MCT-06-0397

Experimental method

X-RAY DIFFRACTION (2.24 Å)