Development of small-molecule probes that selectively kill cells induced to express mutant RAS.
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.
The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, United States.
Michel
M
Weïwer
Joshua A
JA
Bittker
Timothy A
TA
Lewis
Kenichi
K
Shimada
Wan Seok
WS
Yang
Lawrence
L
MacPherson
Sivaraman
S
Dandapani
Michelle
M
Palmer
Brent R
BR
Stockwell
Stuart L
SL
Schreiber
Benito
B
Munoz
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
D054852:Small Molecule Libraries; D013876:Thiophenes; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)