Quantitative phenotypic and pathway profiling guides rational drug combination strategies.
Quantitative phenotypic and pathway profiling guides rational drug combination strategies.
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DOI：
10.3389/fphar.2014.00118
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发表时间：
2014
影响因子：
5.6
通讯作者：
Carragher NO
中科院分区：
文献类型：
--
作者：
Dawson JC;Carragher NO
基于靶点的药物发现策略的进展使学术界和工业界的药物发现小组能够非常有效地产生对单一靶点具有强效和选择性的分子。然而，从最近的临床试验中令人失望的结果已经变得明显的是，开发用于治疗复杂多因素疾病的成功靶向疗法的主要挑战是克服患者中靶向机制的异质性和固有或获得性耐药性。因此，还原论的靶向药物发现方法并不适合于识别和优化复杂疾病的多靶向治疗或合理的药物组合。在这篇文章中，我们描述了新兴的高含量的表型分析和分析工具，以支持剂量比矩阵筛选后的药物组合性能的稳健评价的应用。我们进一步描述了如何将高通量反相蛋白质微阵列与表型筛选相结合，可以提供合理的药物组合假设，但也证实了新的药物组合的作用机制，以促进未来的临床前和临床开发策略。
Advances in target-based drug discovery strategies have enabled drug discovery groups in academia and industry to become very effective at generating molecules that are potent and selective against single targets. However, it has become apparent from disappointing results in recent clinical trials that a major challenge to the development of successful targeted therapies for treating complex multifactorial diseases is overcoming heterogeneity in target mechanism among patients and inherent or acquired drug resistance. Consequently, reductionist target directed drug-discovery approaches are not appropriately tailored toward identifying and optimizing multi-targeted therapeutics or rational drug combinations for complex disease. In this article, we describe the application of emerging high-content phenotypic profiling and analysis tools to support robust evaluation of drug combination performance following dose-ratio matrix screening. We further describe how the incorporation of high-throughput reverse phase protein microarrays with phenotypic screening can provide rational drug combination hypotheses but also confirm the mechanism-of-action of novel drug combinations, to facilitate future preclinical and clinical development strategies.
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影响因子：
11.2
作者：
Iadevaia S;Lu Y;Morales FC;Mills GB;Ram PT
通讯作者：
Ram PT
影响因子：
28.2
作者：
Held MA;Langdon CG;Platt JT;Graham-Steed T;Liu Z;Chakraborty A;Bacchiocchi A;Koo A;Haskins JW;Bosenberg MW;Stern DF
通讯作者：
Stern DF
影响因子：
16.2
作者：
Jabbour, Serge A.;Hardy, Elise;Parikh, Shamik
通讯作者：
Parikh, Shamik
影响因子：
--
作者：
Cubitt, Christopher L.;Menth, Jiliana;Reed, Damon R.
通讯作者：
Reed, Damon R.
影响因子：
46.9
作者：
Lehar, Joseph;Krueger, Andrew S.;Avery, William;Heilbut, Adrian M.;Johansen, Lisa M.;Price, E. Roydon;Rickles, Richard J.;Short, Glenn F., III;Staunton, Jane E.;Jin, Xiaowei;Lee, Margaret S.;Zimmermann, Grant R.;Borisy, Alexis A.
通讯作者：
Borisy, Alexis A.