Patent Watch

November 18, 2013

CK2 may be an attractive target for cancer treatment. C. E. Chuaqui and co-inventors describe pyrrolo[1,5-a]pyrimidine derivatives represented by formula 1. These compounds inhibit casein kinase 2 (CK2) and may potentially be used to prevent and treat CK2-related conditions and diseases, including cancer.

CK2 is a serine- and threonine-selective protein kinase that exists as a tetramer of two catalytic (α and/or α′) subunits and two regulatory (β) subunits. The level of CK2 in normal cells is tightly regulated to perform a variety of essential roles such as cell cycle control and cellular differentiation and proliferation; it also promotes cell survival by modulating apoptotic pathways. 

Elevated levels of CK2 are associated with cancer. Targeted overexpression of CK2 in transgenic animal models results in neoplastic growth. CK2 phosphorylates and regulates the activity and stability of many tumor-suppressor proteins such as PML, p53, and PTEN; oncogenes; and transcriptional activators such as c-Myc, c-Myb, c-Jun, NFκB, and β-catenin. 

Recent studies found evidence that CK2 can suppress apoptosis by phosphorylating pro-apoptotic proteins, which protect the proteins from caspase-mediated cleavage. Inhibiting CK2 also sensitizes cells to TRAIL-receptor–mediated apoptosis, ionizing radiation, and chemotherapeutic agents. (TRAIL is TNF-related apoptosis-inducing ligand; TNF is tumor necrosis factor.)

Inhibiting CK2 may be an effective therapeutic target for treating cancer. The currently available small-molecule CK2 inhibitors, however, lack the necessary balance of potency, selectivity, and druglike properties to be considered as therapeutic agents. The CK2 inhibitors described in this patent application may have improved properties that could provide a useful cancer treatment.

The inventors describe the synthesis of examples 2 and 3 in the figure and the trifluoroacetate salt of example 2. They evaluated the compounds by using the CK2 in vitro mobility shift assay, the HCT-116 72 h AlamarBlue cell-proliferation assay, and a cell-based assay to determine antiproliferative effects on cancer cells in combination with EGFR inhibitors. HCT-116 is a strain of human colon cancer cells; EGFR is the epidermal growth factor receptor. Data for examples 2 and 3 from the first two assays are shown in the table.

Example CK2,
IC50 (mM)
GI501 (μM)
2 <0.004 0.030
3 <0.003 0.009
1. GI50 is the concentration that causes 50%
reduction in the proliferation of cancer cells.

(AstraZeneca AB [Södertälje, Sweden]. WIPO Publication 2013144532, Oct 3, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

View patent information from CAplus(SM) database.

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General formula and representative examples of CK2 inhibitors