Identification of a novel NAMPT inhibitor by CRISPR/Cas9 chemogenomic profiling in mammalian cells.
Identification of a novel NAMPT inhibitor by CRISPR/Cas9 chemogenomic profiling in mammalian cells.
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DOI：
10.1038/srep42728
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发表时间：
2017-02-16
影响因子：
4.6
通讯作者：
Hoepfner D
中科院分区：
文献类型：
--
作者：
Estoppey D;Hewett JW;Guy CT;Harrington E;Thomas JR;Schirle M;Cuttat R;Waldt A;Gerrits B;Yang Z;Schuierer S;Pan X;Xie K;Carbone W;Knehr J;Lindeman A;Russ C;Frias E;Hoffman GR;Varadarajan M;Ramadan N;Reece-Hoyes JS;Wang Q;Chen X;McAllister G;Roma G;Bouwmeester T;Hoepfner D
化学基因组分析是一种强有力的和公正的方法来阐明药理学目标和生物活性化合物的机制。直到最近，由于缺乏哺乳动物全基因组缺失集合，这种性质的全基因组高分辨率实验一直限于真菌系统。以新型烟酰胺磷酸核糖基转移酶（NAMPT）抑制剂为例，我们证明了CRISPR/Cas9系统能够生成瞬时纯合和杂合缺失文库，并允许鉴定介导与化合物作用机制相关的超敏反应和抗性的功效靶标和途径。
Chemogenomic profiling is a powerful and unbiased approach to elucidate pharmacological targets and the mechanism of bioactive compounds. Until recently, genome-wide, high-resolution experiments of this nature have been limited to fungal systems due to lack of mammalian genome-wide deletion collections. With the example of a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, we demonstrate that the CRISPR/Cas9 system enables the generation of transient homo- and heterozygous deletion libraries and allows for the identification of efficacy targets and pathways mediating hypersensitivity and resistance relevant to the compound mechanism of action.