Abstract：
Protein kinase CK2 is a holoenzyme composed of two regulatory subunits (CK2β) and two catalytic subunits (CK2α and CK2α\'). CK2 controls several cellular processes, including proliferation, inflammation, and cell death. However, CK2α and CK2α\' possess different expression patterns and substrates and therefore impact each of these processes differently. Elevated CK2α participates in the development of cancer, while increased CK2α\' has been associated with neurodegeneration, especially Huntington\'s disease (HD). HD is a fatal disease for which no effective therapies are available. Genetic deletion of CK2α\' in HD mouse models has ameliorated neurodegeneration. Therefore, pharmacological inhibition of CK2α\' presents a promising therapeutic strategy for treating HD. However, current CK2 inhibitors are unable to discriminate between CK2α and CK2α\' due to their high structural homology, especially in the targeted ATP-binding site. Using computational analyses, we found a potential type IV (\"D\" pocket) allosteric site that contained different residues between CK2α and CK2α\' and was distal from the ATP-binding pocket featured in both kinases. We decided to look for allosteric modulators that might interact in a biased fashion with the type IV pocket on both CK2α and CK2α\'. We screened a commercial library containing ∼29,000 allosteric-kinase-inhibitor-like compounds using a CK2α\' activity-dependent ADP-Glo Kinase assay. Obtained hits were counter-screened against CK2α using the ADP-Glo Kinase assay, revealing two CK2α\'-biased compounds. These two compounds might serve as the basis for further medicinal chemistry optimization for the potential treatment of HD.
摘要：
蛋白激酶CK2是由两个调节亚基(CK2β)和两个催化亚基(CK2α和CK2α')组成的全酶。CK2控制几个细胞过程，包括扩散，炎症,细胞死亡。然而,CK2α和CK2α具有不同的表达模式和底物，因此对每个过程的影响不同。升高的CK2α参与了癌症的发展,虽然CK2α的增加与神经变性有关，尤其是亨廷顿病（HD）。HD是一种致命的疾病，没有有效的治疗方法。HD小鼠模型中CK2α的遗传缺失改善了神经变性。因此,CK2α的药理学抑制为治疗HD提供了有希望的治疗策略。然而,目前的CK2抑制剂由于其高度的结构同源性而无法区分CK2α和CK2α，特别是在靶向的ATP结合位点。使用计算分析，我们发现了一个潜在的IV型（“D”口袋）变构位点，该位点在CK2α和CK2α之间包含不同的残基，并且远离两种激酶中的ATP结合口袋。我们决定寻找可能与CK2α和CK2α上的IV型口袋以偏置方式相互作用的变构调节剂。我们使用CK2α\'活性依赖性ADP-Glo激酶测定法筛选了一个含有约29,000个变构激酶抑制剂样化合物的商业文库。使用ADP-Glo激酶测定法对CK2α进行反筛选，揭示了两个CK2α偏向的化合物。这两种化合物可能作为进一步药物化学优化的基础，用于HD的潜在治疗。
