Ranking Differential Drug Activities from Dose-Response Synthetic Lethality Screens.
Ranking Differential Drug Activities from Dose-Response Synthetic Lethality Screens.
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DOI：
10.1177/1087057116644890
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发表时间：
2016-10
影响因子：
--
通讯作者：
Ferrer M
中科院分区：
文献类型：
--
作者：
Guha R;Mathews Griner LA;Keller JM;Zhang X;Fitzgerald D;Antignani A;Pastan I;Thomas CJ;Ferrer M
合成致死筛检用于发现新的癌症联合治疗方法。在传统的高通量合成致死筛选中，化合物是在单一剂量下进行测试的，命中选择是基于被测试化合物功效差异的阈值活性值。合成致死筛选的单剂量筛选的局限性在于，它不允许对具有广泛效力和功效的化合物集合的不同活性进行强有力的检测。因此，有必要发展筛选方法，以便能够根据效力和功效的变化来鉴定具有合成致死作用的化合物。在这里，我们描述了基于剂量反应的合成致死筛选的实施，以发现增强或减轻免疫毒素蛋白（HA22）细胞毒性作用的药物。我们开发了一个基于剂量-反应参数的数据分析框架，用于选择具有增强或减轻细胞毒性活性的化合物。数据分析框架包括一个集成排序方法，该方法允许以非参数方式使用多个剂量-反应参数。定量高通量筛选（HTS）能够鉴定出单剂量HTS无法鉴定出的具有合成致死活性的化合物。
Synthetic lethal screens are used to discover new combination treatments for cancer. In traditional high-throughput synthetic lethal screens, compounds are tested at a single dose, and hit selection is based on threshold activity values from the variance of the efficacy of the compounds tested. The limitation of the single-dose screening for synthetic lethal screens is that it does not allow for the robust detection of differential activities from compound collections with a broad range of potencies and efficacies. There is therefore a need to develop screening approaches that enable the identification of compounds with synthetic lethal effects based on changes in both potency and efficacy. Here we describe the implementation of a dose response–based synthetic lethal screen to find drugs that enhance or mitigate the cytotoxic effect of an immunotoxin protein (HA22). We developed a data analysis framework for the selection of compounds with enhancing or mitigating cytotoxic activities based on the use of dose-response parameters. The data analysis framework includes an ensemble ranking approach that allows the use of multiple dose-response parameters in a nonparametric fashion. Quantitative high-throughput screening (HTS) enables the identification of compounds with synthetic lethal activity not identified by single-dose HTS.
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DOI：
10.2174/1875397301004010057
发表时间：
2010-10-21
期刊：
Current chemical genomics
影响因子：
--
作者：
Wang Y;Jadhav A;Southal N;Huang R;Nguyen DT
通讯作者：
Nguyen DT
影响因子：
120.1
作者：
Chan, Denise A.;Giaccia, Amato J.
通讯作者：
Giaccia, Amato J.
影响因子：
--
作者：
Mathews LA;Keller JM;Goodwin BL;Guha R;Shinn P;Mull R;Thomas CJ;de Kluyver RL;Sayers TJ;Ferrer M
通讯作者：
Ferrer M
影响因子：
--
作者：
Fisher, RA
通讯作者：
Fisher, RA
影响因子：
45.3
作者：
Kreitman, Robert J.;Tallman, Martin S.;Pastan, Ira
通讯作者：
Pastan, Ira