Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase

Sheldon Holder, Marina Zemskova, Chao Zhang, Maryam Tabrizizad, Ryan Bremer, Jonathan W. Neidigh, Michael B. Lilly

Research output: Contribution to journalArticle

129 Citations (Scopus)

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 (IC50, 0.34 μmol/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 (ED50, 5.5 μmol/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.

Original languageEnglish (US)
Pages (from-to)163-172
Number of pages10
JournalMolecular cancer therapeutics
Volume6
Issue number1
DOIs
StatePublished - Jan 1 2007

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Phosphotransferases
Proto-Oncogene Proteins c-pim-1
Prostatic Neoplasms
Protein-Serine-Threonine Kinases
Hydrogen Bonding
Growth
quercetagetin
Oncogenes
Flavonoids
Inhibitory Concentration 50
Prostate
Lymphoma
Leukemia
Adenosine Triphosphate
Epithelial Cells
Enzyme-Linked Immunosorbent Assay
Ligands
Cell Line
Enzymes
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Holder, Sheldon ; Zemskova, Marina ; Zhang, Chao ; Tabrizizad, Maryam ; Bremer, Ryan ; Neidigh, Jonathan W. ; Lilly, Michael B. / Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase. In: Molecular cancer therapeutics. 2007 ; Vol. 6, No. 1. pp. 163-172.
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Holder, S, Zemskova, M, Zhang, C, Tabrizizad, M, Bremer, R, Neidigh, JW & Lilly, MB 2007, 'Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase', Molecular cancer therapeutics, vol. 6, no. 1, pp. 163-172. https://doi.org/10.1158/1535-7163.MCT-06-0397

Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase. / Holder, Sheldon; Zemskova, Marina; Zhang, Chao; Tabrizizad, Maryam; Bremer, Ryan; Neidigh, Jonathan W.; Lilly, Michael B.

In: Molecular cancer therapeutics, Vol. 6, No. 1, 01.01.2007, p. 163-172.

Research output: Contribution to journalArticle

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