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  • Many PIM inhibitors have been reported to date

    2020-05-22

    Many PIM inhibitors have been reported to date [7], [8], [9] however, none of them has been marketed so far. SGI-1776 is a representative first-generation PIM inhibitor, which had been under clinical trials for leukemia and prostate cancer [10]. While most of the first-generation PIM inhibitors are PIM1-selective, there is currently great interest in the potential of pan-PIM inhibitors to treat cancer because the three PIM kinases are reported to function redundantly [11]. Representative pan-PIM inhibitors are AZD1208 from AstraZeneca, [12] and PIM447 from Novartis [11]. Clinical trials of PIM447 are underway [11]. Among several classes of CK2 inhibitors effectively inhibiting the growth of tumor cells in vitro at low micromolar ranges are derivatives of benzotriazole and benzimidazole e.g. 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt), 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi), 4,5,6,7-tetrabromo-1H-benzimidazole-2-N,N-dimethylamine (DMAT), 4,5,6,7-tetraiodo-1H-benzimidazole (TIBI), (Ki 23 nM), and one of the most efficient CK2 and PIM dual inhibitors TDB (Ki 32 nM, and 86 nM respectively) [13], [14]. Studies conducted by us [15], as well as others [14] show that CK2 inhibitors frequently exhibit similar inhibitory activity against the PIM1 kinase due to structural similarities within the structures of both kinases [16]. CX-4945 (Silmitasertib), the first ATP-competitive CK2 kinase inhibitor that is currently in Phase I/II clinical trials, also inhibits in vitro not only CK2 kinase activity, but also PIM1 and PIM2 kinase with IC50 values of 0.048 and 0.186 μM, respectively [7], [17]. Recent studies have shown that the use of dual inhibitors (CK2 and PIM inhibition) results in reduced proliferation and induction of apoptosis in human T lymphoblastoid cells (CML) and their multidrug resistant variant (R-CEM), human cervical cancer cells (HeLa) [14] as well as some other cell lines [18]. We previously found that the introduction of a methyl group on the C2 DMPO of TBBi led to the 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole (2MeTBBi) with a promising inhibitory activity of CK2 and PIM1 and with increased cytotoxicity against CCRF-CEM and MCF-7 cells [19]. Here we report the experimental details of the synthesis of a new series aminoalkyl derivatives of TBBt, TBBi and 2MeTBBi. The inhibitory activity of the synthesized compounds was tested using a standard isoptopic kinase assay and the selectivity of selected compounds against a panel of 8 kinases was determined and compared with selectivity of known inhibitors. The Antiproliferative activity of new compounds was tested against three different cancer cell lines. A crystallographic study of CK2α-inhibitor complexes was performed in order to investigate the enzyme/inhibitor interactions.
    Results and discussion
    Conclusions In summary, a series of new aminoalkyl-TBBi and TBBt derivatives were synthesized by reduction of the corresponding azidoalkyl-derivatives with quite reasonable yields. The novel aminoalkyl-TBBi derivatives 8b-c inhibit the activity of CK2 holoenzyme and the PIM1 as effectively as TBBi, while the derivatives of 2MeTBBi (11), compounds 14a-b exerted superior inhibition of PIM1 kinase. The aminoalkyl-TBBt derivatives 9c-d and 10b-d appeared to be weaker inhibitors of CK2 but a little stronger inhibitors of PIM1 than parent TBBt. Evaluation of anti-proliferative activities against CCRF-CEM, MCF-7 and PC-3 human cancer cell lines provided however very interesting results. New alkylamine-derivatives of TBBi and TBBt reduce the viability of cancer cells much more strongly than their parent compounds. Particularly interesting properties have shown derivatives of 2MeTBBi (11), compounds 14a-b, which inhibit the viability of tumor cells even more effectively than the known and approved for clinical trials compound CX-4945. These studies provide evidence for the effectiveness of developing therapies based on the mechanism of a combination of CK2 and PIM kinase inhibitors in the treatment of cancer.