Identification of Biologically Active PDE11-Selective Inhibitors Using a Yeast-Based High-Throughput Screen
Identification of Biologically Active PDE11-Selective Inhibitors Using a Yeast-Based High-Throughput Screen
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DOI：
10.1016/j.chembiol.2011.12.010
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发表时间：
2012-01-27
影响因子：
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通讯作者：
Hoffman, Charles S.
中科院分区：
文献类型：
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作者：
Ceyhan, Ozge;Birsoy, Kivanc;Hoffman, Charles S.
环核苷酸磷酸二酯酶11（PDE11）的生物学作用知之甚少，部分原因是缺乏选择性抑制剂。为了满足对此类化合物的需求，我们使用基于酵母的生长测定法完成了对PDE 11抑制剂的类似于200，000化合物的高通量筛选（HTS），并鉴定了4种有效且选择性的PDE 11抑制剂。一种化合物，沿着两种结构类似物，提高人肾上腺皮质细胞中的cAMP和皮质醇水平，与将PDE 11活性与肾上腺功能联系起来的基因关联研究一致。因此，这些化合物可以立即用作研究细胞培养中PDE 11功能的化学工具，并导致开发用于治疗肾上腺皮质功能障碍的疗法。我们的研究结果进一步验证了这种基于酵母的HTS平台用于发现有效的、选择性的和生物活性的PDE抑制剂。
The biological roles of cyclic nucleotide phosphodiesterase 11 (PDE11) enzymes are poorly understood, in part due to the lack of selective inhibitors. To address the need for such compounds, we completed an similar to 200,000 compound high-throughput screen (HTS) for PDE11 inhibitors using a yeast-based growth assay, and identified 4 potent and selective PDE11 inhibitors. One compound, along with two structural analogs, elevates cAMP and cortisol levels in human adrenocortical cells, consistent with gene association studies that link PDE11 activity to adrenal function. As such, these compounds can immediately serve as chemical tools to study PDE11 function in cell culture, and as leads to develop therapeutics for the treatment of adrenal insufficiencies. Our results further validate this yeast-based HTS platform for the discovery of potent, selective, and biologically active PDE inhibitors.