Bittker Joshua A, Weiwer Michel, Lewis Tim, Shimada Kenichi, Yang Wan S, MacPherson Lawrence, Dandapani Sivaraman, Munoz Ben, Palmer Michelle, Stockwell Brent R, Schreiber Stuart L
The Broad Institute Probe Development Center, Cambridge, MA
Howard Hughes Medical Institute, Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY
Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing engineered cell lines, with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the Molecular Libraries Small Molecule Repository (MLSMR) against immortalized BJ fibroblasts expressing HRAS followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the oncogene. A new chemical class was identified that had improved potency compared with previously known RAS selective compounds. The most potent and selective of these, probe ML210, displayed nanomolar potency in the primary screening cell line while maintaining selectivity similar to previously identified probes. The probe is in a novel structural class in the field of RAS synthetically lethal compounds and will, therefore, be highly useful in identifying pathways that can potentially be used for selectively inhibiting cancer cells.
合成致死筛选是一种化学生物学方法，用于鉴定能选择性杀死表达癌基因的工程细胞系的小分子，目的是识别出针对癌细胞提供特定靶点的信号通路。我们对来自分子文库小分子储存库（MLSMR）的303282种化合物进行了高通量筛选，筛选对象是表达HRAS的永生化BJ成纤维细胞，随后在一系列缺乏该癌基因的同基因细胞中对致死性化合物进行反筛选。我们鉴定出了一个新的化学类别，与先前已知的RAS选择性化合物相比，其效力有所提高。其中最有效和最具选择性的探针ML210，在初次筛选细胞系中显示出纳摩尔级别的效力，同时保持了与先前鉴定的探针相似的选择性。该探针属于RAS合成致死化合物领域中的一种新型结构类别，因此在识别可能用于选择性抑制癌细胞的信号通路方面将非常有用。
