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Screen for RAS-Selective Lethal Compounds and VDAC Ligands - Probe 1.


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2010 Mar 26 [updated 2011 Feb 10].

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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
Howard Hughes Medical Institute, Chemistry & Chemical Biology, Harvard University, Cambridge, MA


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 chemical class was identified that had improved potency and specificity compared to previously known selective compounds. The most potent and selective of these, probe CID 3689413/ML162, displayed nanomolar potency in the primary screening cell line. Despite an essential common reactive group in the probe and analogs, significant selective lethality has been observed in the engineered as well as other cell lines. This probe will, therefore, be highly useful in identifying pathways that can potentially be used for selectively inhibiting cancer cells.

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