2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 1. Identification of an Allosteric Binding Site.
2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 1. Identification of an Allosteric Binding Site.
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2 - 氨基噻唑衍生物作为蛋白激酶CK2的选择性别构调节剂。1. 一个别构结合位点的鉴定
DOI：
10.1021/acs.jmedchem.8b01766
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发表时间：
2019-02-28
影响因子：
7.3
通讯作者：
Lomberget T
中科院分区：
文献类型：
--
作者：
Bestgen B;Krimm I;Kufareva I;Kamal AAM;Seetoh WG;Abell C;Hartmann RW;Abagyan R;Cochet C;Le Borgne M;Engel M;Lomberget T
CK2是一种普遍存在的丝氨酸/苏氨酸蛋白激酶，参与控制各种信号通路，并且已知具有组成活性。在本研究中，我们确定了芳基2-氨基噻唑作为一类新的CK2抑制剂，它表现出非atp竞争的作用模式，并稳定了溶液中CK2的非活性构象。酶动力学研究、STD-NMR、圆二色光谱和天然质谱实验表明，这些化合物结合在atp结合位点外的变构口袋中。我们的数据，结合分子对接研究，强烈表明这个新的结合位点位于αC螺旋和柔性甘氨酸富环之间的界面。首次优化得到的化合物7对纯化的CK2α的IC50为3.4 μM，具有良好的选择性。因此，我们确定了一类针对变构口袋的新型CK2抑制剂，为进一步优化抗癌药物提供了巨大的潜力。
CK2 is a ubiquitous Ser/Thr protein kinase involved in the control of various signaling pathways and is known to be constitutively active. In the present study, we identified aryl 2-aminothiazoles as a novel class of CK2 inhibitors, which displayed a non ATP-competitive mode of action and stabilized an inactive conformation of CK2 in solution. Enzyme kinetics studies, STD-NMR, circular dichroism spectroscopy and native mass spectrometry experiments demonstrated that the compounds bind in an allosteric pocket outside the ATP-binding site. Our data, combined with molecular docking studies, strongly suggested that this new binding site was located at the interface between the αC helix and the flexible glycine-rich loop. A first hit optimization led to compound 7, exhibiting an IC50 of 3.4 μM against purified CK2α in combination with a favorable selectivity profile. Thus, we identified a novel class of CK2 inhibitors targeting an allosteric pocket, offering great potential for further optimization into anti-cancer drugs.
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影响因子：
3.6
作者：
Gottlieb, HE;Kotlyar, V;Nudelman, A
通讯作者：
Nudelman, A
影响因子：
8.4
作者：
Brear P;De Fusco C;Hadje Georgiou K;Francis-Newton NJ;Stubbs CJ;Sore HF;Venkitaraman AR;Abell C;Spring DR;Hyvönen M
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Hyvönen M
影响因子：
3.2
作者：
Enkvist, Erki;Viht, Kaido;Uri, Asko
通讯作者：
Uri, Asko
影响因子：
3.7
作者：
Kim H;Choi K;Kang H;Lee SY;Chi SW;Lee MS;Song J;Im D;Choi Y;Cho S
通讯作者：
Cho S
DOI：
10.1073/pnas.0708800104
发表时间：
2007-12-18
影响因子：
11.1
作者：
Fedorov, Oleg;Marsden, Brian;Knapp, Stefan
通讯作者：
Knapp, Stefan