Golub Andriy G, Yakovenko Olexander Ya, Bdzhola Volodymyr G, Sapelkin Vladislav M, Zien Piotr, Yarmoluk Sergiy M
Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, 150 Zabolotny str., Kyiv 03143, Ukraine.
J Med Chem. 2006 Nov 2;49(22):6443-50. doi: 10.1021/jm050048t.
Due to the emerging role of protein kinase CK2 as a molecule that participates not only in the development of some cancers but also in viral infections and inflammatory failures, small organic inhibitors of CK2, besides application in scientific research, may have therapeutic significance. In this paper, we present a new class of CK2 inhibitors-3-carboxy-4(1H)-quinolones. This class of inhibitors has been selected via receptor-based virtual screening of the Otava compound library. It was revealed that the most active compounds, 5,6,8-trichloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7) (IC(50) = 0.3 microM) and 4-oxo-1,4-dihydrobenzo[h]quinoline-3-carboxylic acid (9) (IC(50) = 1 microM), are ATP competitive (K(i) values are 0.06 and 0.28 microM, respectively). Evaluation of the inhibitors on seven protein kinases shows considerable selectivity toward CK2. According to theoretical calculations and experimental data, a structural model describing the key features of 3-carboxy-4(1H)-quinolones responsible for tight binding to CK2 active site has been developed.
由于蛋白激酶CK2不仅在某些癌症的发展中起作用，还参与病毒感染和炎症失调，因此CK2的小分子有机抑制剂除了在科学研究中的应用外，可能还具有治疗意义。在本文中，我们介绍了一类新型的CK2抑制剂——3-羧基-4(1H)-喹诺酮类。这类抑制剂是通过基于受体的Otava化合物库虚拟筛选而选出的。结果表明，活性最高的化合物，5,6,8-三氯-4-氧代-1,4-二氢喹啉-3-羧酸（7）（IC(50) = 0.3 microM）和4-氧代-1,4-二氢苯并[h]喹啉-3-羧酸（9）（IC(50) = 1 microM），具有ATP竞争性（K(i)值分别为0.06和0.28 microM）。对这七种蛋白激酶抑制剂的评估显示出对CK2具有相当高的选择性。根据理论计算和实验数据，已建立了一个描述3-羧基-4(1H)-喹诺酮类与CK2活性位点紧密结合的关键特征的结构模型。
