Unprecedented Selectivity and Structural Determinants of a New Class of Protein Kinase CK2 Inhibitors in Clinical Trials for the Treatment of Cancer
Unprecedented Selectivity and Structural Determinants of a New Class of Protein Kinase CK2 Inhibitors in Clinical Trials for the Treatment of Cancer
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DOI：
10.1021/bi2008382
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发表时间：
2011-10-04
期刊：
影响因子：
2.9
通讯作者：
Pinna, Lorenzo A.
中科院分区：
文献类型：
--
作者：
Battistutta, Roberto;Cozza, Giorgio;Pinna, Lorenzo A.
5-(3-氯苯氨基)苯并[c][2，6]萘啶-8-羧酸(CX-4945)是治疗癌症的第一个临床阶段的蛋白激酶CK2抑制剂，是一类新的CK2抑制剂的代表，其K-I值在低纳摩尔范围内，与其他激酶相比具有前所未有的选择性。本文报道了CX-4945及其两个类似物(CX-5011和CX-5279)与人CK2催化亚基的配合物的晶体结构。与它们的ATP竞争抑制模式一致，这三个化合物都结合在CK2(I型抑制剂)的活性部位。抑制剂的三环支架叠加在ATP的腺嘌呤上，与结合腔建立多个疏水相互作用。与ATP相比，更延伸的支架允许所有三个配体共享的羧基功能渗透到活性部位的最深处，在那里它与保守的水W1和Lys-68相互作用，从而解释了这个带负电荷的基团在赋予这类抑制剂高效力方面的关键作用。CX-5011和CX-5279中嘧啶的存在而不是吡啶(如在CX-4945中)的存在可能解释了这些化合物更高的特异性，其基尼系数通过对102和/或235K组的分析计算出显著高于CX-4945(分别为0.735和0.755，对0.615)，这是迄今为止报道的CK2抑制剂的最高选择性。
5-(3-Chlorophenylamino)benzo[c] [2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer, is representative of a new class of CK2 inhibitors with K-i values in the low nanomolar range and unprecedented selectivity versus other kinases. Here we present the crystal structure of the complexes of CX-4945 and two analogues (CX-5011 and CX-5279) with the catalytic subunit of human CK2. Consistent with their ATP-competitive mode of inhibition, all three compounds bind in the active site of CK2 (type I inhibitors). The tricyclic scaffold of the inhibitors superposes on the adenine of ATP, establishing multiple hydrophobic interactions with the binding cavity. The more extended scaffold, as compared to that of ATP, allows the carboxylic function, shared by all three ligands, to penetrate into the deepest part of the active site where it makes interactions with conserved water W1 and Lys-68, thus accounting for the crucial role of this negatively charged group in conferring high potency to this class of inhibitors. The presence of a pyrimidine in CX-5011 and in CX-5279 instead of a pyridine (as in CX-4945) ring is likely to account for the higher specificity of these compounds whose Gini coefficients, calculated by profiling them against panels of 102 and/or 235 kinases, are significantly higher than that of CX-4945 (0.735 and 0.755, respectively, vs 0.615), marking the highest selectivity ever reported for CK2 inhibitors.