Structural insight into human CK2α in complex with the potent inhibitor ellagic acid

doi:10.1016/j.bmcl.2009.04.076

Bioorganic & Medicinal Chemistry Letters

Volume 19, Issue 11, 1 June 2009, Pages 2920-2923

https://doi.org/10.1016/j.bmcl.2009.04.076 Get rights and content

Abstract

We determined the 2.35-Å crystal structure of a human CK2 catalytic subunit (referred to as CK2α complexed with the ATP-competitive, potent CK2 inhibitor ellagic acid. The inhibitor binds to CK2α with a novel binding mode, including water-mediated hydrogen bonds. This structural information may support discovery of potent CK2 inhibitors.

Graphical abstract

2.35 Å X-ray crystal structure reveals that ellagic acid binds to human CK2α with a novel binding mode including four water mediated interactions and induces a specific conformation at His160.

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Acknowledgments

These studies are supported by the Program of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO). The synchrotron radiation experiments were done at Photon Factory with the approval of the Japan Synchrotron Radiation Research Institute. We thank the staff for their help in data collection at the BL-6A station.

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Discovery of ellagic acid as a competitive inhibitor of Src homology phosphotyrosyl phosphatase 2 (SHP2) for cancer treatment: In vitro and in silico study
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Targeting SHP2 has become a potential cancer treatment strategy. In this study, ellagic acid was first reported as a competitive inhibitor of SHP2, with an IC₅₀ value of 0.69 ± 0.07 μM, and its inhibitory potency was 34.86 times higher that of the positive control NSC87877. Ellagic acid also had high inhibitory activity on the SHP2-E76K and SHP2-E76A mutants, with the IC₅₀ values of 1.55 ± 0.17 μM and 0.39 ± 0.05 μM, respectively. Besides, the IC₅₀ values of ellagic acid on homologous proteins SHP1, PTP1B, and TCPTP were 0.93 ± 0.08 μM, 2.04 ± 0.28 μM, and 11.79 ± 0.83 μM, with selectivity of 1.35, 2.96, and 17.09 times, respectively. The CCK8 proliferation experiment exhibited that ellagic acid would inhibit the proliferation of various cancer cells. It was worth noting that the combination of ellagic acid and KRAS^G12C inhibitor AMG510 would produce a strong synergistic effect in inhibiting NCI-H358 cells. Western blot experiment exhibited that ellagic acid would downregulate the phosphorylation levels of Erk and Akt in NCI-H358 and MDA-MB-468 cells. Molecular docking and molecular dynamics studies revealed the binding information between SHP2 and ellagic acid. In summary, this study provides new ideas for the development of SHP2 inhibitors.
Bivalent binding mode of an amino-pyrazole inhibitor indicates the potentials for CK2α1-selective inhibitors
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The structures reveal the potentials for the design of potent and selective CK2α1 inhibitors. Crystals of the CK2α1 and CK2α2 complexes were prepared by co-crystallization or soaking with 3-amino-5-[1-cyano-2-(1H-indol-3-yl)eth-1-en-1-yl]-2H-pyrrazole-4-carbonitrile (AG1112, Fig. 1) (Sigma-Aldrich, St. Louis, Missouri) according to published methods [11,12]. X-ray diffraction data sets were collected at the BL44XU beamline of SPring-8 in Japan and integrated by XDS [13].
Casein kinase 2 (CK2) is a vital protein kinase that consists of two catalytic subunits (CK2α1 and/or CK2α2) and two regulatory subunits (CK2β). CK2α1 is a drug target for nephritis and cancers, while CK2α2 is a serious off-target because its inhibition causes testicular toxicity. High similarity between the isozymes CK2α1 and CK2α2 make it difficult to design CK2α1-specific inhibitors. Herein, the crystal structures of CK2α1 and CK2α2 complexed with a 3-amino-pyrazole inhibitor revealed the remarkable differences in the protein–inhibitor interaction modes. This inhibitor bound to the ATP binding sites of both isozymes in apparently distinct orientations. In addition, another molecule of this inhibitor bound to CK2α1, but not to CK2α2, at the CK2β protein–protein interface. Binding energy calculations and biochemical experiments suggested that this inhibitor possesses the conventional ATP-competitive characteristics with moderate allosteric function in a molecular glue mechanism. These results will assist the potential design of potent and selective CK2α1 inhibitors.
1,2,4-Triazolin-5-thione derivatives with anticancer activity as CK1γ kinase inhibitors
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Molecular docking was performed with Standard precision (SP) method of Glide [52] of Schrödinger suite of software. Crystal structures of CK1 isoform γ3 (PDB ID: 2IZR) [53] and CK2α (PDB ID: 2ZJW) [54] were used for molecular docking. Grid files were generated based on co-crystallized inhibitors with default settings.
The optimization and synthesis of new CK2 and CK1 inhibitors are the basis for the development of new therapeutic strategies for the treatment of cancer and neurodegenerative disorders associated with overexpression and abnormal functioning of these enzymes. Triazole derivatives appear to be especially interesting as potential kinase inhibitors. In this context we synthesized a series of 1,2,4-triazolin-5-thione derivatives as CK1γ kinase inhibitors. The antiproliferative activity of synthesized compounds was assessed against cancer cells: human lung adenocarcinoma (A549), human hepatoma (HepG2), and human breast adenocarcinoma (MCF-7). Compound 1 exhibited antiproliferative potency against A549 cancer cells and was characterized by a selective antiproliferative effect. Additionally, this compound has high apoptotic activity against A549, HepG2, MCF-7 cells and induced only slight amount of necrotic cells in these cell lines. In order to decipher the mechanism of anticancer activity of the studied compounds PASS software was used and these compounds were assayed for the inhibition of CK1γ and CK2α kinases. The reported series of 1,2,4-triazolin-5-thiones inhibits CK1γ and CK2α kinases in micromolar range. The most active compound shows activity against isoform γ3 which at concentration of 50 μM reduced the kinase activity by 69% while at 100 μM by 80%. CK2α was found to be less susceptible to the effects of the triazoles tested, as the reduction in kinase activity by 29% was observed for compound 15, and by 27% for compound 1 only at the concentration of 100 μM. The inhibition of CK1γ and CK2α kinases was rationalized using molecular docking.
Identification of protein kinase CK2 inhibitors using solvent dipole ordering virtual screening
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The prism-shaped crystals of the complexes were obtained by the sitting-drop vapor diffusion method using ethylene glycol as the precipitant. This condition was the same as that used for solving the ellagic acid-CK2α complex [55]. Diffraction data were collected at the BL17A station of the Photon Factory, or at the BL44XU station of the SPring-8 at 100 K.
Novel protein kinase CK2 inhibitors were identified using the solvent dipole ordering virtual screening method. A total of 26 compounds categorized in 15 distinct scaffold classes inhibited greater than 50% of enzyme activity at 50 μM, and eight exhibited IC₅₀ values less than 10 μM. Most of the identified compounds are lead-like and dissimilar to known inhibitors. The crystal structures of two of the CK2 complexes revealed the high accuracy of the predicted binding modes.
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Crystal structure of human CK2α at 1.06 Å resolution
2013, Journal of Synchrotron Radiation

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Structural insight into human CK2α in complex with the potent inhibitor ellagic acid

Abstract

Graphical abstract

Section snippets

Acknowledgments

Biochim. Biophys. Acta

Adv. Enzyme Regul.

J. Mol. Biol.

FEBS Lett.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

Chem. Biol.

J. Mol. Biol.

J. Mol. Biol.

FASEB J.

EMBO J.