Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United States.
Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, Minnesota 55414, United States.
ACS Chem Neurosci. 2024 Aug 7;15(15):2703-2718. doi: 10.1021/acschemneuro.4c00062. Epub 2024 Jun 22.
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.
蛋白激酶 CK2 是一种由两个调节亚基（CK2β）和两个催化亚基（CK2α 和 CK2α'）组成的全酶。CK2 控制着多种细胞过程，包括增殖、炎症和细胞死亡。然而，CK2α 和 CK2α' 具有不同的表达模式和底物，因此对这些过程的影响也不同。升高的 CK2α 参与癌症的发生，而增加的 CK2α' 与神经退行性变有关，特别是亨廷顿病（HD）。HD 是一种致命的疾病，目前尚无有效的治疗方法。在 HD 小鼠模型中基因敲除 CK2α' 可改善神经退行性变。因此，抑制 CK2α' 的药理学方法为治疗 HD 提供了一种很有前途的治疗策略。然而，由于 CK2α 和 CK2α' 的结构高度同源，尤其是在靶向 ATP 结合位点，目前的 CK2 抑制剂无法区分它们。通过计算分析，我们发现了一个潜在的第四种（“D”口袋）变构位点，该位点在 CK2α 和 CK2α' 之间包含不同的残基，并且远离两种激酶都具有的 ATP 结合口袋。我们决定寻找可能以偏向方式与 CK2α 和 CK2α' 的第四种口袋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包含约 29000 种变构激酶抑制剂样化合物的商业文库。获得的命中化合物使用 ADP-Glo 激酶测定法针对 CK2α 进行了再次筛选，发现了两种 CK2α' 偏向化合物。这两种化合物可能为进一步的药物化学优化提供基础，以潜在治疗 HD。
