Department für Chemie, Institut für Biochemie, Universität zu Köln, Zülpicher Str. 47, D-50674 Köln, Germany.
Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, PharmaCampus, Corrensstr. 48, D-48149 Münster, Germany.
J Med Chem. 2022 Jan 27;65(2):1302-1312. doi: 10.1021/acs.jmedchem.1c00063. Epub 2021 Jul 29.
CK2α and CK2α' are paralogous catalytic subunits of CK2, which belongs to the eukaryotic protein kinases. CK2 promotes tumorigenesis and the spread of pathogenic viruses like SARS-CoV-2 and is thus an attractive drug target. Efforts to develop selective CK2 inhibitors binding offside the ATP site had disclosed the αD pocket in CK2α; its occupation requires large conformational adaptations of the helix αD. As shown here, the αD pocket is accessible also in CK2α', where the necessary structural plasticity can be triggered with suitable ligands even in the crystalline state. A CK2α' structure with an ATP site and an αD pocket ligand guided the design of the bivalent CK2 inhibitor KN2. It binds to CK2 with low nanomolar affinity, is cell-permeable, and suppresses the intracellular phosphorylation of typical CK2 substrates. Kinase profiling revealed a high selectivity of KN2 for CK2 and emphasizes the selectivity-promoting potential of the αD pocket.
CK2α 和 CK2α' 是 CK2 的同工催化亚基，属于真核蛋白激酶。CK2 促进肿瘤发生和 SARS-CoV-2 等致病病毒的传播，因此是一个有吸引力的药物靶点。开发结合 ATP 结合位点之外的选择性 CK2 抑制剂的努力揭示了 CK2α 中的 αD 口袋；它的占据需要 αD 螺旋的大构象适应。如这里所示，αD 口袋在 CK2α'中也可及，其中在晶体状态下，适当的配体甚至可以触发必要的结构可塑性。具有 ATP 结合位点和 αD 口袋配体的 CK2α'结构指导了双价 CK2 抑制剂 KN2 的设计。它以低纳摩尔亲和力与 CK2 结合，可穿透细胞，并抑制典型 CK2 底物的细胞内磷酸化。激酶分析揭示了 KN2 对 CK2 的高选择性，并强调了 αD 口袋的选择性促进潜力。
