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  • br Conclusion In this review we

    2021-01-11


    Conclusion In this review, we have discussed how inhibition of the CK2/CDK5 signaling axis protects WM only when inhibited before ischemia, while inhibition of the CK2/AKT/GSK3β signaling axis protects WM either before or after an ischemic injury in young, aging, and old WM (Fig. 3). CK2 activation mediates WM ischemic injury in a differential spatiotemporal manner such that CDK5 signaling becomes important during ischemia, while AKT signaling emerges as the main pathway during the reperfusion period following ischemia. Consequently, interventions selectively targeting the activated form of AKT confer post-ischemic functional recovery in young and aging WM. In contrast, ischemia-mediated regulation of CK2 activity impacts neuronal survival differently. The reasons for this discrepancy may stem from differences in the dominant CK2 substrates, the duration of the CK2 inhibition, the involvement of inflammation, and the choice of CK2 pharmacological inhibitor used in these studies. As the role of CK2 in the control of apoptosis in non-neuronal cells is well-established, we would advocate, based on our results in WM, that future studies use a selective CK2 inhibitor like CX-4945 at an optimal concentration and duration. Experiments using a short duration of treatment with CX-4945 to investigate neuronal survival in an in vivo model are also warranted. Until then, the effective use of CK2 signaling inhibition to protect the rilpivirine against ischemic injury will require the development of a targeted approach for WM in order to minimize damage to GM. It is essential to preserve, protect, and repair both neuronal and glial cells of the brain to improve functional recovery. Nevertheless, continued research into the role of CK2 signaling in WM may reveal more effective therapeutic targets for WM that may be useful for neurodegenerative diseases that primarily affect glial cells and myelin such as traumatic brain injury, multiple sclerosis, periventricular leukomalacia, and spinal cord injury.
    Introduction Protein kinase CK2 is a serine/threonine protein kinase responsible for the phosphorylation of more than 300 physiological substrates, and plays important roles in cell cycle progression and multiple signal transduction pathways [1,2]. Increasing evidence suggests that deregulation of CK2 is associated with cancer, including hematological malignancies [3,4]. Consequently, this kinase has emerged as an attractive therapeutic target for the development of inhibitors with potential clinical use. A wide range of CK2 ATP-competitive inhibitors with different scaffolds has been reported, including tricyclic quinolone derivatives, benzimidazoles, pyrazol-triazines, coumarins, anthaquinones and phenyl-azoles [5,6]. However, so far, only CX-4945 has advanced through clinical trials [7], while most of the other inhibitors have low selectivity and toxicity and are thus impeded from clinical use [[8], [9], [10]]. Attempts to optimize CK2 ATP-competitive inhibitors presenting polycyclic scaffolds have faced challenges to overcome these drawbacks. Here we pursue a strategy to discover more potent CK2 inhibitors with novel non-polycyclic scaffolds that permit exploration of diverse pharmacophoric fragments. Natural products provide the important pharmaceutical leads because of their structural diversity and a broad-spectrum of biological activities. Flavonoids [11], emodin [12] and coumarin [13] have been previously reported as CK2 inhibitors, but it is chemically challenging to introduce a wide range of groups on these scaffolds [14,15]. Here we have explored the potential of natural product derivatives with a linear scaffold, 2-propenone, as a novel class of CK2 ATP-competitive inhibitors. These newly synthesized compounds are analogs of isoliquiritigenin (ISL), a natural product containing 2-propenone that exhibits anti-proliferation activity on cervical, breast, lung, liver and prostate cancers cells [16,17]. To evaluate the potential of these 2-propenone derivatives as CK2 inhibitors, we firstly used a fragment assembly-based strategy [18,19] by combining amine-substituted five-membered heterocyclic moieties and benzoic acid as pharmacophore fragments. These novel compounds were further tested for their CK2 inhibitory activities and anti-proliferation effects on HepG-2 cancer cells.