Pietsch Markus, Viht Kaido, Schnitzler Alexander, Ekambaram Ramesh, Steinkrüger Michaela, Enkvist Erki, Nienberg Christian, Nickelsen Anna, Lauwers Miriam, Jose Joachim, Uri Asko, Niefind Karsten
Institut II für Pharmakologie, Zentrum für Pharmakologie, Medizinische Fakultät, Universität zu Köln, Gleueler Str. 24, D-50931 Köln, Germany.
Institute of Chemistry, University of Tartu, 14A Ravila St., 50411 Tartu, Estonia.
Bioorg Chem. 2020 Mar;96:103608. doi: 10.1016/j.bioorg.2020.103608. Epub 2020 Jan 23.
Protein kinase CK2, a heterotetrameric holoenzyme composed of two catalytic chains (CK2α) attached to a homodimer of regulatory subunits (CK2β), is a target for drug development for cancer therapy. Here, we describe the tetraiodobenzimidazole derivative ARC-3140, a bisubstrate inhibitor addressing the ATP site and the substrate-binding site of CK2 with extraordinary affinity (K = 84 pM). In a crystal structure of ARC-3140 in complex with CK2α, three copies of the inhibitor are visible, one of them at the CK2β interface of CK2α. Subsequent interaction studies based on microscale thermophoresis and fluorescence anisotropy changes revealed a significant impact of ARC-3140 and of its tetrabromo equivalent ARC-1502 on the CK2α/CK2β interaction. A structural inspection revealed that ARC-3140, unlike CK2β antagonists described so far, interferes with both sub-interfaces of the bipartite CK2α/CK2β interaction. Thus, ARC-3140 is a lead for the further development of highly effective compounds perturbating the quaternary structure of the CK2αβ holoenzyme.
蛋白激酶CK2是一种异源四聚体全酶，由两个催化链（CK2α）与一个调节亚基同二聚体（CK2β）相连组成，是癌症治疗药物开发的一个靶点。在此，我们描述了四碘苯并咪唑衍生物ARC-3140，一种双底物抑制剂，它以非凡的亲和力（K = 84 pM）作用于CK2的ATP位点和底物结合位点。在ARC-3140与CK2α复合物的晶体结构中，可以看到三个抑制剂分子，其中一个位于CK2α的CK2β界面处。随后基于微量热泳和荧光各向异性变化的相互作用研究表明，ARC-3140及其四溴类似物ARC-1502对CK2α/CK2β相互作用有显著影响。结构检查发现，与迄今为止描述的CK2β拮抗剂不同，ARC-3140干扰了二元CK2α/CK2β相互作用的两个亚界面。因此，ARC-3140是进一步开发扰乱CK2αβ全酶四级结构的高效化合物的先导物。
