Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase
Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase
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DOI：
10.1158/1535-7163.mct-06-0397
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发表时间：
2007-01-01
影响因子：
5.7
通讯作者：
Lilly, Michael B.
中科院分区：
文献类型：
--
作者：
Holder, Sheldon;Zemskova, Marina;Lilly, Michael B.
Pim-1激酶是一种真正的癌基因，与白血病、淋巴瘤和前列腺癌的发展有关，也是药物开发计划的靶点。我们已经使用实验方法确定了一种选择性的、细胞渗透性的、小分子的Pim-1激酶抑制剂，以促进对该酶的基础和翻译研究。我们使用了一种基于酶联免疫吸附试验的方法来筛选潜在的激酶抑制剂的多样性文库。3，3‘，4’，5，6，7-羟基黄酮(3，3‘，4’，5，6，7-羟基黄酮)是一种中等强度的三磷酸腺苷竞争性抑制物(IC50，0.34mU/L)。对PIM1与槲皮黄素或其他两种黄酮类化合物的络合物的晶体结构的解析表明，尽管这些配体具有很强的相似性，但它们的结合位置和氢键模式都有很大的差别。与PIM2和其他7种丝氨酸苏氨酸激酶相比，Quercetagetin是PIM1的高度选择性抑制剂。在完整的RWPE2前列腺癌细胞中，Quercetagetin对PIM1活性的抑制作用呈剂量依赖性(ED50，5.5MU/L)。用Quercetagetin处理的RWPE2细胞在抑制PIM1激酶活性的抑制浓度下表现出明显的生长抑制。此外，Quercetagetin抑制其他前列腺上皮细胞系生长的能力与它们的PIM1蛋白水平成正比。Quercetagetin可以作为Pim-1激酶的中等效力和选择性的细胞渗透性抑制剂，并可能有助于概念验证研究，以支持临床有用的PIM1抑制剂的开发。
The pim-1 kinase is a true oncogene that has been implicated in the development of leukemias, lymphomas, and prostate cancer, and is the target of drug development programs. We have used experimental approaches to identify a selective, cell-permeable, small-molecule inhibitor of the pim-1 kinase to foster basic and translational studies of the enzyme. We used an ELISA-based kinase assay to screen a diversity library of potential kinase inhibitors. The flavonol quercetagetin (3,3',4',5,6,7-hydroxyflavone) was identified as a moderately potent, ATP-competitive inhibitor (IC50, 0.34 mu mol/L). Resolution of the crystal structure of PIM1 in complex with quercetagetin or two other flavonoids revealed a spectrum of binding poses and hydrogen-bonding patterns in spite of strong similarity of the ligands. Quercetagetin was a highly selective inhibitor of PIM1 compared with PIM2 and seven other serine-threonine kinases. Quercetagetin was able to inhibit PIM1 activity in intact RWPE2 prostate cancer cells in a dose-dependent manner (ED50, 5.5 mu mol/L). RWPE2 cells treated with quercetagetin showed pronounced growth inhibition at inhibitor concentrations that blocked PIM1 kinase activity. Furthermore, the ability of quercetagetin to inhibit the growth of other prostate epithelial cell lines varied in proportion to their levels of PIM1 protein. Quercetagetin can function as a moderately potent and selective, cell-permeable inhibitor of the pim-1 kinase, and may be useful for proof-of-concept studies to support the development of clinically useful PIM1 inhibitors.