Development of small-molecule probes that selectively kill cells induced to express mutant RAS

Abstract Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing 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 National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRAS G12V followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRAS G12V oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4–23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells.