Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure
Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure
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DOI：
10.1016/j.bmcl.2006.09.038
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发表时间：
2006-12-15
影响因子：
2.7
通讯作者：
Shapiro, Paul
中科院分区：
文献类型：
--
作者：
Chen, Fengming;Hancock, Chad N.;Shapiro, Paul
细胞外信号调节激酶（ERK 1和ERK 2）是细胞增殖的重要介质。ERK蛋白的组成性激活在许多人类癌症的增殖中起关键作用。利用最近确定的底物对接结构域的ERK 2，我们已经使用计算机辅助药物设计（CADD），以确定新的低分子量化合物与ERK 2相互作用的ATP-独立的方式和破坏底物特异性的相互作用。在目前的研究中，使用活性磷酸化ERK 2蛋白的3D结构的CADD筛选来鉴定抑制性化合物。我们在ERK特异性磷酸化、细胞增殖和结合试验中测试了通过CADD筛选鉴定的13种化合物。在测试的13种化合物中，4种化合物强烈抑制ERK介导的核糖体S6激酶-1（Rsk-1）和/或转录因子Elk-1的磷酸化，并抑制HeLa宫颈癌细胞的增殖，IC 50值在2-10 μ M范围内。这些研究表明，CADD可用于识别先导化合物，用于开发对活性ERK及其与参与癌细胞增殖的底物的相互作用具有选择性的新型非ATP依赖性抑制剂。(c)2006爱思唯尔有限公司保留所有权利。
The extracellular signal-regulated kinases (ERK1 and ERK2) are important mediators of cell proliferation. Constitutive activation of the ERK proteins plays a critical role in the proliferation of many human cancers. Taking advantage of recently identified substrate docking domains on ERK2, we have used computer-aided drug design (CADD) to identify novel low molecular weight compounds that interact with ERK2 in an ATP-independent manner and disrupt substrate-specific interactions. In the current study, a CADD screen of the 3D structure of active phosphorylated ERK2 protein was used to identify inhibitory compounds. We tested 13 compounds identified by the CADD screen in ERK-specific phosphorylation, cell proliferation, and binding assays. Of the 13 compounds tested, 4 compounds strongly inhibited ERK-mediated phosphorylation of ribosomal S6 kinase-1 (Rsk-1) and/or the transcription factor Elk-1 and inhibited the proliferation of HeLa cervical carcinoma cells with IC50 values in the 2-10 mu M range. These studies demonstrate that CADD can be used to identify lead compounds for development of novel non-ATP-dependent inhibitors selective for active ERK and its interactions with substrates involved in cancer cell proliferation. (c) 2006 Elsevier Ltd. All rights reserved.