Systems cell biology knowledge created from high content screening
Systems cell biology knowledge created from high content screening
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DOI：
10.1089/adt.2005.3.501
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发表时间：
2005-10-01
影响因子：
1.8
通讯作者：
Taylor, DL
中科院分区：
文献类型：
--
作者：
Giuliano, KA;Cheung, WS;Taylor, DL
高含量筛选（HCS），大规模自动化分析的时间和空间变化的细胞和细胞阵列中的细胞成分，有可能创造巨大的系统细胞生物学知识库。HCS沿着早期药物发现过程的连续性，包括使用新知识促进决策过程的先导优化。我们展示了使用多路复用HCS测定来建立新的系统细胞生物学知识的方法，该测定是在知识挖掘工具的帮助下设计的，以测量一组人类肿瘤细胞类型对一组天然产物衍生的微管靶向抗癌剂及其合成类似物的表型反应。我们展示了这种新的系统细胞生物学知识如何可以用于设计一种先导化合物优化策略，用于小组的至少两个成员，（-）-laulimalide和（+）-discodermolide，该策略利用细胞杀伤活性，同时最小限度地干扰细胞周期的调节和微管的稳定性。此外，这种方法也可以应用于细胞的基础生物医学研究。
High content screening (HCS), the large-scale automated analysis of the temporal and spatial changes in cells and cell constituents in arrays of cells, has the potential to create enormous systems cell biology knowledge bases. HCS is being employed along with the continuum of the early drug discovery process, including lead optimization where new knowledge is being used to facilitate the decision-making process. We demonstrate methodology to build new systems cell biology knowledge using a multiplexed HCS assay, designed with the aid of knowledge-mining tools, to measure the phenotypic response of a panel of human tumor cell types to a panel of natural product-derived microtubule-targeted anticancer agents and their synthetic analogs. We show how this new systems cell biology knowledge can be used to design a lead compound optimization strategy for at least two members of the panel, (-)-laulimalide and (+)-discodermolide, that exploits cell killing activity while minimally perturbing the regulation of the cell cycle and the stability of microtubules. Furthermore, this methodology can also be applied to basic biomedical research on cells.