CK2 is a Ser/Thr-protein kinase playing a crucial role in promoting cell growth and survival, hence it is considered a promising target for anti-cancer drugs. However, many previously reported CK2 inhibitors lack selectivity. In search of novel scaffolds for selective CK2 inhibition, we identified a dihydropyrido-thieno[2,3-d]pyrimidine derivative displaying submicromolar inhibitory activity against CK2α. This scaffold captured our interest because of the basic secondary amine, a rather unusual motif for CK2 inhibitors. Our optimization strategy comprised the incorporation of a 4-piperazinyl moiety as a linker group and introduction of varying substituents on the pendant phenyl ring. All resulting compounds exhibited potent CK2α inhibition, with IC₅₀ values in the nanomolar range. Compound 10b demonstrated the most balanced activity profile with a cell-free IC₅₀ value of 36.7 nM and a notable cellular activity with a GI₅₀ of 7.3 μM and 7.5 μM against 786-O renal cell carcinoma and U937 lymphoma cells, respectively. 10b displayed excellent selectivity when screened against a challenging kinase selectivity profiling panel. Moreover, 10b inhibited CK2 in the cells, albeit less potently than CX-4945, but induced cell death more strongly than CX-4945. Altogether, we have identified a novel CK2 inhibitory scaffold with drug-like physicochemical properties in a favorable basic pKa range.

中文翻译：

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发现一种新的选择性 CK2 抑制剂类别，具有不寻常的基本支架


CK2 是一种 Ser/Thr 蛋白激酶，在促进细胞生长和存活方面起着至关重要的作用，因此被认为是抗癌药物的一个有前途的靶点。然而，许多先前报道的 CK2 抑制剂缺乏选择性。在寻找选择性 CK2 抑制的新型支架时，我们鉴定了一种二氢嘧啶-噻吩并[2,3-d] 嘧啶衍生物，对 CK2α 表现出亚微摩尔抑制活性。这个支架引起了我们的兴趣，因为碱性仲胺是 CK2 抑制剂的一个相当不寻常的基序。我们的优化策略包括将 4-哌嗪基团作为连接基团掺入，并在悬垂苯基环上引入不同的取代基。所有所得化合物均表现出有效的 CK2α 抑制作用，IC₅₀ 值在纳摩尔范围内。化合物 10b 表现出最平衡的活性谱，无细胞 IC₅₀ 值为 36.7 nM，对 786-O 肾细胞癌和 U937 淋巴瘤细胞的 GI₅₀ 分别为 7.3 μM 和 7.5 μM。10B 在针对具有挑战性的激酶选择性分析面板进行筛选时表现出优异的选择性。此外，10b 抑制细胞中的 CK2，尽管不如 CX-4945 有效，但比 CX-4945 更强烈地诱导细胞死亡。总之，我们已经确定了一种新的 CK2 抑制支架，在有利的碱性 pKa 范围内具有类似药物的物理化学特性。