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  • Based on the above we hypothesized


    Based on the above, we hypothesized that a PROTAC strategy would be effective to induce CK2 protein degradation. Herein salubrinal mg reported is an approach for the preparation of novel PROTACs via “click reaction” for degradation of CK2 protein (Fig. 2). Importantly, “click reaction” is a very facile, selective and “green” reaction with the aim of binding two molecules together under mild water-tolerant conditions. CX-4945, a selective CK2 inhibitor with a strong binding force stemming from hydrophobic interactions of flat tricyclic core with binding pocket residues, hydrogen bonding of pyridine nitrogen with the NH of Val116 in the hinge region, and an ionic bridge with Lys68, was first elected as CK2 targeting ligand [24]. And pomalidomide was applied as a recruiter of E3 ligase to conjugate with CX-4945 via different linkers by click reaction. It was worth noting that the number of alkyl chains was important for PROTACs, because the length of the chain has a great influence on the interaction between E3 ligase and CK2 protein.
    Results and discussion
    Conclusions We have reported the design and synthesis of four CK2 targeting compounds composed of a CK2 inhibitor CX-4945 and pomalidomide, which are connected by alkyl linkers via click reactions. Among them, compound 2 exhibited a strong PROTAC feature. As a CK2 protein degrader, compound 2 degrades the protein in a dose and time-dependent manner, and can maintain CK2 at a low basal level. And the degrader degrades the protein through an ubiquitin and proteasome-dependent proteolysis pathway. The degradation of CK2 by compound 2 resulted in a series of changes in its downstream proteins which include the reduced phosphorylation of Akt (a phosphorylated substrate of CK2) and the up-regulation of p53 (a tumor suppressor protein). Significantly, 2 also possessed similar cytotoxicity to CX-4945 toward CK2 overexpressed cancer salubrinal mg like MDA-MB-231, but its mechanism of action is quite different from the inhibitor. Owing to the overexpression of CK2 in most tumors with highly pleiotropic features, and more obvious influence on the downstream proteins of CK2 during a shorter time period triggered by PROTAC, targeting CK2 degradation will have potential applications for cancer treatments.
    Experimental section
    Introduction Protein kinases catalyze the transfer of phosphate groups from adenosine triphosphate (ATP) to serine, threonine, or tyrosine residues of target proteins. This phosphorylation is an important stage in regulation of cell growth, cellular signal transduction, cell differentiation, and influences apoptotic mechanisms. Deregulation of protein kinases activity or expression is implicated in a number of diseases, including cancer, diabetes, and inflammation. Thus, targeted inhibition of the deregulated protein kinases has become an attractive therapeutic strategy in cancer therapy. Casein kinase 2 (CK2) and PIM kinase (Proviral Integration site of Moloney Virus) belong to the serine/threonine kinases family and their overexpression is frequently associated with acute myeloid leukemia, and a variety of cancers including prostate, breast or/and lung cancers [1], [2]. The high activity of these kinases in cancer cells is associated with inhibition of apoptosis, suggesting a protective role of CK2 and PIM1 in programmed cell death. Recent studies have shown that the contribution of CK2 and PIM1 kinases in regulation of transcription, differentiation, or signaling of DNA damage/repair systems is achieved by regulating survival pathways. For example, both kinases participate in an activation of the transcriptional factor NF-κB, observed in transformed cells [3], [4]. Elevated level of CK2 induces abnormal activation of NF-κB, which in turn contributes to the development of breast cancer [5]. Moreover, the tumor transformation of lymphocytes with PIM involvement is dependent on activation of NF-κB [4]. Downregulation of these kinases by chemical methods promotes apoptosis in cells [6], indicating CK2 and PIM1 kinases as molecular targets in the development of new therapeutic agents.