Proposed allosteric inhibitors bind to the ATP site of CK2a
Proposed allosteric inhibitors bind to the ATP site of CK2a
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提议的变构抑制剂与 CK2a 的 ATP 位点结合
DOI：
10.1101/2020.07.07.191353
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Brear P
中科院分区：
文献类型：
--
作者：
Brear P
CK 2 α是一种普遍存在的、研究充分的激酶，是小分子抑制的靶点，用于治疗癌症。虽然已经描述了许多不同类型的腺苷5′-三磷酸（ATP）竞争性抑制剂用于CK 2 α，但它们往往具有显著的脱靶活性，因此需要新的方法。最近，一系列CK 2 α抑制剂被描述为变构的，作用于先前未鉴定的结合位点。由于这些抑制剂与已知的ATP竞争性抑制剂相似，我们进一步研究了它们。在我们全面的结构和生物物理分析中，我们没有发现这些抑制剂与拟议的变构位点结合的证据。相反，我们报告的晶体结构，竞争性等温滴定量热法（ITC）和NMR，氢氘交换（HDX）质谱，和化学信息学分析，都指向这些化合物结合在ATP口袋。我们的结果和实验方法与原始报告中的数据比较表明，差异的主要原因是聚集的非特异性抑制。
CK2α is a ubiquitous, well-studied kinase that is a target for small-molecule inhibition, for treatment of cancers. While many different classes of adenosine 5′-triphosphate (ATP)-competitive inhibitors have been described for CK2α, they tend to suffer from significant off-target activity and new approaches are needed. A series of inhibitors of CK2α has recently been described as allosteric, acting at a previously unidentified binding site. Given the similarity of these inhibitors to known ATP-competitive inhibitors, we have investigated them further. In our thorough structural and biophysical analyses, we have found no evidence that these inhibitors bind to the proposed allosteric site. Rather, we report crystal structures, competitive isothermal titration calorimetry (ITC) and NMR, hydrogen–deuterium exchange (HDX) mass spectrometry, and chemoinformatic analyses that all point to these compounds binding in the ATP pocket. Comparisons of our results and experimental approach with the data presented in the original report suggest that the primary reason for the disparity is nonspecific inhibition by aggregation.