7,7′-Diazaindirubin-A small molecule inhibitor of casein kinase 2 in vitro and in cells
7,7′-Diazaindirubin-A small molecule inhibitor of casein kinase 2 in vitro and in cells
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DOI：
10.1016/j.bmc.2013.11.031
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发表时间：
2014-01-01
影响因子：
3.5
通讯作者：
Eisenbrand, Gerhard
中科院分区：
文献类型：
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作者：
Cheng, Xinlai;Merz, Karl-Heinz;Eisenbrand, Gerhard
氮杂-和二氮杂-双吲哚分别通过7-氮杂红、7-氮杂吲哚、7-氮杂吲哚乙酸酯及其非氮杂对应物的偶联合成。虽然 7,7'-二氮杂靛蓝 (10) 和 7,7'-二氮杂异靛蓝 (11) 在浓度高达 100 μM 的几种人类肿瘤细胞系中未表现出抗增殖活性，但在 LXFL529L 细胞（人大细胞肺肿瘤）中，7-氮杂红宾 (12) 和 7'-氮杂红宾 (13) 比母体分子靛红更具活性。异种移植物）和 7,7'-二氮杂红红素 (14) 在这些细胞中表现出显着增强的生长抑制活性。在 NCI 60 细胞系组中，14 个细胞优先在某些黑色素瘤和非小细胞肺癌细胞中表现出抗增殖活性。与靛玉红所观察到的有效丝氨酸/苏氨酸/酪氨酸激酶抑制相反，220 种激酶中的 14 种激酶抑制谱显示，大多数激酶的激酶抑制活性很大程度上丧失，仅少数激酶保留了抑制活性。在1μM浓度下，尤其是酪蛋白激酶CK1γ3、CK2α、CK2α2和SIK被抑制超过50％。在基于细胞的检测中，14 显着影响各种人类肿瘤细胞中 CK2 介导的信号传导。在 MCF7 细胞中，14 诱导细胞周期停滞在 G1 和 G2/M 以及细胞凋亡，而 CK2 缺陷的 MCF7 细胞具有耐药性。这些发现揭示了 14 的一种新的关键作用机制，表明 CK2 抑制主要与人类肿瘤细胞的生长抑制存在因果关系。 (C) 2013 Elsevier Ltd. 保留所有权利。
Aza- and diaza-bisindoles were synthesized by coupling of 7-azaisatin, 7-azaoxindol, 7-azaindoxyl acetate, and their non-aza counterparts, respectively. Whereas 7,7'-diazaindigo (10) and 7,7'-diazaisoindigo (11) did not show antiproliferative activity in several human tumor cell lines up to 100 mu M, 7-azaindirubin (12) and 7'-azaindirubin (13) were more active than the parent molecule, indirubin, in LXFL529L cells (human large cell lung tumor xenograft), and 7,7'-diazaindirubin (14) was exhibiting substantially enhanced growth inhibitory activity in these cells. In the NCI 60 cell line panel, 14 displayed antiproliferative activity preferentially in certain melanoma and non-small cell lung cancer cells. In contrast to the potent serine/threonine/tyrosine kinase inhibition observed for indirubins, kinase inhibition profiling of 14 in 220 kinases revealed largely a loss of kinase inhibitory activity towards most kinases, with retained inhibitory activity for just a few kinases. At 1 mu M concentration, especially casein kinases CK1 gamma 3, CK2 alpha, CK2 alpha 2, and SIK were inhibited by more than 50%. In cell-based assays, 14 markedly affected CK2-mediated signaling in various human tumor cells. In MCF7 cells, 14 induced cell cycle arrest at G1 and G2/M and apoptosis, whereas CK2-deficient MCF7 cells were resistant. These findings reveal a novel key mechanism of action for 14, suggesting primarily CK2 inhibition to be causally related to growth inhibition of human tumor cells. (C) 2013 Elsevier Ltd. All rights reserved.