Department of Biomedical Sciences, University of Padova, Padua, Italy.
Cell Mol Life Sci. 2014 Aug;71(16):3173-85. doi: 10.1007/s00018-013-1552-5. Epub 2014 Jan 18.
It has been proposed that dual inhibitors of protein kinases CK2 and PIM-1 are tools particularly valuable to induce apoptosis of cancer cells, a property, however, implying cell permeability, which is lacking in the case of selective CK2/PIM-1 inhibitors developed so far. To fill this gap, we have derivatized the scaffold of the promiscuous CK2 inhibitor TBI with a deoxyribose moiety, generating TDB, a selective, cell-permeable inhibitor of CK2 and PIM-1. Here, we shed light on the structural features underlying the potency and narrow selectivity of TDB by exploiting a number of TDB analogs and by solving the 3D structure of the TDB/CK2 complex at 1.25 Å resolution, one of the highest reported so far for this kinase. We also show that the cytotoxic efficacy of TDB is almost entirely due to apoptosis, is accompanied by parallel inhibition of cellular CK2 and PIM-1, and is superior to both those observed combining individual inhibitors of CK2 and PIM-1 and by treating cells with the CK2 inhibitor CX4945. These data, in conjunction with the observations that cancer cells are more susceptible than non-cancer cells to TDB and that such a sensitivity is maintained in a multi-drug resistance background, highlight the pharmacological potential of this compound.
有人提出，双重蛋白激酶 CK2 和 PIM-1 抑制剂是特别有价值的工具，可以诱导癌细胞凋亡，然而，这种特性意味着细胞通透性，而到目前为止开发的选择性 CK2/PIM-1 抑制剂则缺乏这种特性。为了填补这一空白，我们用脱氧核糖部分衍生了广谱 CK2 抑制剂 TBI 的支架，生成了 TDB，一种选择性、细胞通透的 CK2 和 PIM-1 抑制剂。在这里，我们通过利用一系列 TDB 类似物，并以 1.25Å 的分辨率解决了 TDB/CK2 复合物的 3D 结构（迄今为止报道的最高分辨率之一），阐明了 TDB 的效力和狭窄选择性的结构特征。我们还表明，TDB 的细胞毒性作用几乎完全归因于细胞凋亡，同时抑制细胞内 CK2 和 PIM-1，并且优于单独使用 CK2 和 PIM-1 抑制剂以及用 CK2 抑制剂 CX4945 处理细胞时观察到的效果。这些数据，加上癌细胞比非癌细胞更容易受到 TDB 的影响，以及在多药耐药背景下保持这种敏感性的观察结果，突出了这种化合物的药理学潜力。
