Discovery of a novel, selective CK2 inhibitor class with an unusual basic scaffold

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2024-11-13 DOI:10.1016/j.ejmech.2024.117048
Hend Khalifa, Ahmed K. ElHady, Ting Liu, Walid A.M. Elgaher, Odile Filhol, Claude Cochet, Ashraf H. Abadi, Mostafa M. Hamed, Mohammad Abdel-Halim, Matthias Engel
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Abstract

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.

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发现具有不寻常基本支架的新型选择性 CK2 抑制剂类别
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,因此被认为是一种很有希望的抗癌药物靶点。然而,之前报道的许多 CK2 抑制剂都缺乏选择性。为了寻找选择性抑制 CK2 的新型支架,我们发现了一种二氢吡啶-噻吩并[2,3-d]嘧啶衍生物,它对 CK2α 具有亚摩尔抑制活性。这个支架引起了我们的兴趣,因为它含有碱性仲胺,这对于 CK2 抑制剂来说是一个相当不寻常的基团。我们的优化策略包括加入一个 4-哌嗪基作为连接基团,并在垂苯环上引入不同的取代基。所有化合物都表现出了强效的 CK2α 抑制作用,IC50 值在纳摩尔范围内。化合物 10b 的活性最为均衡,无细胞 IC50 值为 36.7 nM,对 786-O 肾细胞癌细胞和 U937 淋巴瘤细胞的 GI50 分别为 7.3 μM 和 7.5 μM,具有显著的细胞活性。在针对具有挑战性的激酶选择性分析小组进行筛选时,10b 表现出了极佳的选择性。此外,10b 对细胞中 CK2 的抑制作用虽然不如 CX-4945,但诱导细胞死亡的作用比 CX-4945 更强。总之,我们发现了一种新型的 CK2 抑制支架,它具有类似于药物的理化性质,且基本 pKa 值范围良好。
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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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