Cyclic nucleotide signalling: a molecular approach to drug discovery for Alzheimer's disease
Cyclic nucleotide signalling: a molecular approach to drug discovery for Alzheimer's disease
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DOI：
10.1042/bst0331330
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发表时间：
2005-12-01
影响因子：
3.9
通讯作者：
MacKenzie, SJ
中科院分区：
文献类型：
--
作者：
McPhee, I;Gibson, LCD;MacKenzie, SJ
EPAC（由cAMP直接激活的交换蛋白）蛋白是GEF（鸟嘌呤核苷酸交换因子），其在与cAMP结合时激活Rap GTP酶。这些蛋白质参与许多疾病，神经变性，炎症和代谢，已经开始显示它们如何被证明是治疗干预的重要靶点。当我们发现EPAC 1和EPAC 2的表达水平在与阿尔茨海默病相关的脑区域中改变时，我们首先对EPAC产生了兴趣[McPhee，Breslin，Kewney，麦肯齐，Cooreman，吉布森和哈蒙德（2004）国际专利号WO 2004/096199 A2]。已知化合物可以设计成对EPAC的选择性超过PKA（蛋白激酶A）;然而，这些化合物都是基于cAMP的核心结构。我们决定筛选一个小的化合物库（10 000种化合物），以研究开发cAMP结构之外的化合物系列的可能性。随后，我们开发了一种新的，高通量的屏幕上的[H-3]cAMP从EPAC cAMP结合位点的位移的基础上，并确定了小分子命中从苏格兰生物医学铅代库。这些化合物选择性地结合到EPAC 1和EPAC 2的cAMP结合位点，并且在结构上与cAMP不同。它们对EPAC 1和EPAC 2具有相似的亲和力，并且对EPAC的特异性高于PKA。我们相信这些化合物为药物优化计划提供了一个有价值的起点。
The EPAC (exchange protein directly activated by cAMP) proteins are GEFs (guanine nucleotide-exchange factors) that activate Rap GTPases upon binding to cAMP. The involvement of these proteins in a number of diseases, neurodegenerative, inflammatory and metabolic, has started to show how they may prove to be important targets for therapeutic intervention. We first became interested in EPAC when we discovered that the expression levels of both EPAC1 and EPAC2 were altered in those regions of the brain associated with Alzheimer's disease [McPhee, Breslin, Kewney, MacKenzie, Cooreman, Gibson and Hammond (2004) International Patent number WO 2004/096199 A2]. it was known that compounds could be designed to be selective for EPAC over PKA (protein kinase A); however, these compounds were all based around the core structure of cAMP. We decided to screen a small compound library (10 000 compounds) to investigate the possibility of developing a compound series outside of the cAMP structure. We subsequently developed a novel, high-throughput screen based on the displacement of [H-3]cAMP from the EPAC cAMP-binding site and identified small molecule hits from the Scottish Biomedical Lead Generation Library. These compounds selectively bind to the cAMP-binding sites of EPAC1 and EPAC2 and are structurally dissimilar to cAMP. They have similar affinities for both EPAC1 and EPAC2 and have a high degree of specificity for EPAC over PKA. We believe that these compounds provide a valuable starting point for a drug optimization programme.