Golub A G, Yakovenko O Ya, Prykhod'ko A O, Lukashov S S, Bdzhola V G, Yarmoluk S M
Department of Combinatorial Chemistry, Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, Kyiv, Ukraine.
Biochim Biophys Acta. 2008 Jan;1784(1):143-9. doi: 10.1016/j.bbapap.2007.10.009. Epub 2007 Nov 20.
Protein kinase CK2 (Casein Kinase 2) is an extremely pleiotropic Ser/Thr kinase with high constitutive activity. The observation of CK2 deregulations in various pathological processes suggests that CK2 inhibitors may have a therapeutic value, particularly as anti-neoplastic and antiviral drugs. Here, we present the 4,5,6,7-tetrahalogeno-1H-isoindole-1,3(2H)-diones as a novel potent class of CK2 inhibitors. We identified this class of inhibitors by high-throughput docking of a compound collection in the ATP-binding site of human CK2. The most active compounds are 2-(4,5,6,7-tetraiodo-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid and 2-(4,5,6,7-tetraiodo-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid with IC(50) values of 0.15 microM and 0.3 microM, respectively. These inhibitors are ATP-competitive and they only minimally inhibit the activities of protein kinases DYRK1a, MSK1, GSK3 and CDK5. Binding modes for the most active inhibitors are proposed.
蛋白激酶CK2（酪蛋白激酶2）是一种具有高度组成性活性的极其多效的丝氨酸/苏氨酸激酶。在各种病理过程中观察到CK2失调表明，CK2抑制剂可能具有治疗价值，特别是作为抗肿瘤和抗病毒药物。在此，我们介绍4,5,6,7-四卤代-1H-异吲哚-1,3(2H)-二酮作为一类新型强效CK2抑制剂。我们通过在人CK2的ATP结合位点对化合物库进行高通量对接来鉴定这类抑制剂。活性最高的化合物是2-(4,5,6,7-四碘-1,3-二氧代-1,3-二氢-2H-异吲哚-2-基)丙酸和2-(4,5,6,7-四碘-1,3-二氧代-1,3-二氢-2H-异吲哚-2-基)乙酸，其IC(50)值分别为0.15 microM和0.3 microM。这些抑制剂是ATP竞争性的，并且它们对蛋白激酶DYRK1a、MSK1、GSK3和CDK5的活性仅有最小程度的抑制。提出了活性最高的抑制剂的结合模式。
