Inhibiting CK2 among Promising Therapeutic Strategies for Gliomas and Several Other Neoplasms

Abstract

In gliomas, casein kinase 2 (CK2) plays a dominant role in cell survival and tumour invasiveness and is upregulated in many brain tumours. Among CK2 inhibitors, benzimidazole and isothiourea derivatives hold a dominant position. While targeting glioma tumour cells, they show limited toxicity towards normal cells. Research in recent years has shown that these compounds can be suitable as components of combined therapies with hyperbaric oxygenation. Such a combination increases the susceptibility of glioma tumour cells to cell death via apoptosis. Moreover, researchers planning on using any other antiglioma investigational pharmaceutics may want to consider using these agents in combination with CK2 inhibitors. However, different compounds are not equally effective when in such combination. More research is needed to elucidate the mechanism of treatment and optimize the treatment regimen. In addition, the role of CK2 in gliomagenesis and maintenance seems to have been challenged recently, as some compounds structurally similar to CK2 inhibitors do not inhibit CK2 while still being effective at reducing glioma viability and invasion. Furthermore, some newly developed inhibitors specific for CK2 do not appear to have strong anticancer properties. Further experimental and clinical studies of these inhibitors and combined therapies are warranted.

Synthesis and Anticancer Activity of Novel Dual Inhibitors of Human Protein Kinases CK2 and PIM-1

“…Next, an exhaustive bromination of the resulting 2 with Br 2 in boiling water performed under irradiation of purple LEDs (390 nm) for 24 h afforded the desired 2,4,5,6,7-pentabromo-1H-benzimidazole (3) in 42% yield. Finally, the aminolysis of the key intermediate 3 was carried out using the appropriate amino alcohol in anhydrous ethanol in a pressure glass tube reactor at elevated temperatures (110-115 • C) to afford DMAT (4) and its derivatives (5)(6)(7)(8)(9)(10)(11) in the yield range of 13-64%. Due to the strong impact of the stereochemistry of xenobiotics on their biological activity in vivo, there is an urgent need to evaluate the single enantiomers of designed inhibitors toward target proteins, as well as cancer cell lines.…”

“…We envisioned that if the eudysmic Scheme 1. Synthesis of amino alcohol-like DMAT derivatives (5)(6)(7)(8)(9)(10)(11) as potential dual CK2/ PIM-1 inhibitors.…”

“…All the resulting products (4)(5)(6)(7)(8)(9)(10)(11) were characterized by single-proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy, high-resolution mass spectrometry (HR-MS), and high-performance liquid chromatography (HPLC). A lack of 13 C-NMR spectra is typical for polyhalogenobenzimidazoles, since recording the narrow signals corresponding to quaternary carbon atoms is highly challenging for these compounds due to the electronic features of the TBB-ring possessing a N-H tautomeric proton.…”

“…Unlike other eukaryotic kinases, both CK2 and PIM-1 demonstrate constitutive activity associated with a lack of phosphorylation sites in the activation loop [ 7 , 8 ]. Overexpression of these kinases occurs in many types of cancers, including leukemia, breast, and prostate cancer [ 9 , 10 , 11 , 12 ]. The increased catalytic activity of PIM-1 and CK2 kinases has been shown to enhance cell resistance to chemotherapy, inter alia, by inactivating BAD protein, a member of the Bcl-2 family [ 13 ], and interacting with the Myc factor [ 14 ].…”

Minor Kinases with Major Roles in Cytokinesis Regulation

“…Because CK2 is constitutively active in eukaryotic cells [ 112 ], its function in cancer development is strictly linked to its overexpression [ 113 ], which reaches particularly high levels in several types of cancer such as breast cancer, lung cancer, prostate cancer, colorectal cancer, renal cancer, various types of leukemia, and glioblastoma [ 114 , 115 ]. The study of CK2 action in cancerogenesis is very complex; indeed, using the PubMed search string “ck2 and cancer”, it is possible to retrieve more than 1000 results, allowing for the identification of hundreds of targets, as previously said [ 116 , 117 ].…”