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Screen for RAS-Selective Lethal Compounds and VDAC Ligands - Probe 2

Publication TypeJournal Article
Year of Publication2010
AuthorsBittker, JA, Weiwer, M, Lewis, T, Shimada, K, Yang, WS, Macpherson, L, Dandapani, S, Munoz, B, Palmer, M, Stockwell, BR, Schreiber, SL
Date Published2010/01/01

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 HRASV12 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.