磷酸二酯酶
药物发现
生物
cGMP特异性磷酸二酯酶5型
癌症
癌细胞
表型筛选
计算生物学
细胞毒性T细胞
表型
生物信息学
体外
基因
生物化学
酶
遗传学
解剖
西地那非
作者
Luc de Waal,Timothy A. Lewis,Matthew G. Rees,Aviad Tsherniak,Xiaoyun Wu,Peter S. Choi,Lara Gechijian,Christina R. Hartigan,Patrick W. Faloon,Mark J. Hickey,Nicola Tolliday,Steven A. Carr,Paul A. Clemons,Benito Muñoz,Bridget K. Wagner,Alykhan F. Shamji,Angela N. Koehler,Monica Schenone,Alex B. Burgin,Stuart L. Schreiber,Heidi Greulich,Matthew Meyerson
标识
DOI:10.1038/nchembio.1984
摘要
High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the gene PDE3A, encoding phosphodiesterase 3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells, whereas others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggestive of a neomorphic activity. Coexpression of SLFN12 with PDE3A correlates with DNMDP sensitivity, whereas depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery.
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