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

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 4; pp. 1822 - 1826
• Main Authors: Weïwer, Michel, Bittker, Joshua A., Lewis, Timothy A., Shimada, Kenichi, Yang, Wan Seok, MacPherson, Lawrence, Dandapani, Sivaraman, Palmer, Michelle, Stockwell, Brent R., Schreiber, Stuart L., Munoz, Benito
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.02.2012; Elsevier
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Cell Line; Cell Line, Tumor; chemistry; Drug Screening Assays, Antitumor; Fibroblasts; Humans; Inhibitory Concentration 50; Medical sciences; MLPCN probes; Molecular Structure; mutants; Mutation; Nitroisoxazole; oncogenes; Pharmacology. Drug treatments; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; RAS oncogene; Rats; screening; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Synthetic lethal; Thiophenes - chemistry; Thiophenes - pharmacology; α-Chloroamide; MLPCN probes; α-Chloroamide; Synthetic lethal; RAS oncogene; Nitroisoxazole; Muscle relaxant; Lanperisone; Chemical structure; Small molecule; Mutation; Onc gene; In vitro
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2011.09.047

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 HRASG12V followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRASG12V 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.