2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action.
2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action.
复制标题
DOI：
10.1021/acs.jmedchem.8b01765
复制
发表时间：
2019-02-28
影响因子：
7.3
通讯作者：
Engel M
中科院分区：
文献类型：
--
作者：
Bestgen B;Kufareva I;Seetoh W;Abell C;Hartmann RW;Abagyan R;Le Borgne M;Filhol O;Cochet C;Lomberget T;Engel M
在过去十年中，蛋白 CK2 作为抗癌药物靶点引起了广泛关注。我们之前描述了催化 α 亚基上新变构位点的鉴定，以及基于 4-(4-苯基噻唑-2-基氨基)苯甲酸支架的第一个小分子配体。在目前的工作中，结合模型引导的结构优化导致了先导化合物 2-羟基-4-((4-(萘-2-基)噻唑-2-基)氨基)苯甲酸 (27) 的鉴定，显示出针对纯化 CK2α 的亚微摩尔效力 (IC50 = 0.6 μM)。此外，27 诱导 786-O 肾细胞癌细胞凋亡和细胞死亡（EC50 = 5 μM），并且比 ATP 竞争性候选药物 CX-4945 更有效地抑制 STAT3 激活（EC50：1.6 μM vs. 5.3 μM）。值得注意的是，我们的变构配体抑制 CK2 的效力因个体底物而异。总而言之，新型变构袋被证明是一个可成药位点，为开发高效、选择性变构 CK2 抑制剂提供了绝佳的前景。
Protein CK2 has gained much interest as an anti-cancer drug target in the last decade. We had previously described the identification of a new allosteric site on the catalytic α-subunit, along with first small molecule ligands based on the 4-(4-phenylthiazol-2-ylamino) benzoic acid scaffold. In the present work, structure optimizations guided by a binding model led to the identification of the lead compound 2-hydroxy-4-((4-(naphthalen-2-yl)thiazol-2-yl)amino)benzoic acid (27), showing a submicromolar potency against purified CK2α (IC50 = 0.6 μM). Furthermore, 27 induced apoptosis and cell death in 786-O renal cell carcinoma cells (EC50 = 5 μM) and inhibited STAT3 activation even more potently than the ATP-competitive drug candidate CX-4945 (EC50s: 1.6 μM vs. 5.3 μM). Notably, the potencies of our allosteric ligands to inhibit CK2 varied depending on the individual substrate. Altogether, the novel allosteric pocket was proved a druggable site, offering an excellent perspective to develop efficient and selective allosteric CK2 inhibitors.
登录
查看更多内容
DOI：
10.3390/ph10010018
发表时间：
2017-01-28
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Chua MM;Ortega CE;Sheikh A;Lee M;Abdul-Rassoul H;Hartshorn KL;Dominguez I
通讯作者：
Dominguez I
影响因子：
3.6
作者：
Gottlieb, HE;Kotlyar, V;Nudelman, A
通讯作者：
Nudelman, A
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
14.8
作者：
Cyphers, Soreen;Ruff, Emily F.;Levinson, Nicholas M.
通讯作者：
Levinson, Nicholas M.
影响因子：
12.4
作者：
Di Maira, G;Salvi, M;Ruzzene, M
通讯作者：
Ruzzene, M