Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Saitama, 351-0198, Japan.
Seed Compounds Exploratory Unit for Drug Discovery Platform, Drug Discovery Platforms Cooperation Division, RIKEN Center for Sustainable Resource Science, Saitama, 351-0198, Japan.
Chembiochem. 2022 Apr 5;23(7):e202100561. doi: 10.1002/cbic.202100561. Epub 2021 Dec 7.
The step of identifying target molecules and elucidating the mode of action of bioactive compounds is a major bottleneck for drug discovery from phenotypic screening. Genetic screening for genes that affect drug sensitivity or phenotypes of mammalian cultured cells is a powerful tool to obtain clues to their modes of action. Chemical genomic screening systems for comprehensively identifying such genes or genetic pathways have been established using shRNA libraries for RNA interference-mediated mRNA knockdown or sgRNA libraries for CRISPR/Cas9-mediated gene knockout. The combination of chemical genomic screening in mammalian cells with other approaches such as biochemical searches for target molecules, phenotypic profiling, and yeast genetics provides a systematic way to elucidate the mode of action by converging various pieces of information regarding target molecules, target pathways, and synthetic lethal pathways.
从表型筛选中发现生物活性化合物的目标分子并阐明其作用模式是药物发现的主要瓶颈。筛选影响药物敏感性或哺乳动物培养细胞表型的基因是获得其作用模式线索的有力工具。使用 shRNA 文库进行 RNA 干扰介导的 mRNA 敲低或 sgRNA 文库进行 CRISPR/Cas9 介导的基因敲除，已经建立了用于全面鉴定此类基因或遗传途径的化学基因组筛选系统。将化学基因组筛选与其他方法（如针对靶分子的生化搜索、表型分析和酵母遗传学）结合使用，为通过汇聚有关靶分子、靶途径和合成致死途径的各种信息来阐明作用模式提供了一种系统的方法。
