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Bioorg Med Chem Lett DOI:10.1016/j.bmcl.2011.09.047

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

Publication TypeJournal Article
Year of Publication2012
AuthorsWeïwer, M, Bittker, JA, Lewis, TA, Shimada, K, Yang, WSeok, MacPherson, L, Dandapani, S, Palmer, M, Stockwell, BR, Schreiber, SL, Munoz, B
JournalBioorg Med Chem Lett
Date Published2012 Feb 15
KeywordsAnimals, Apoptosis, Cell Line, Cell Line, Tumor, Drug Screening Assays, Antitumor, Fibroblasts, Humans, Inhibitory Concentration 50, Molecular Structure, Mutation, Proto-Oncogene Proteins p21(ras), Rats, Small Molecule Libraries, Structure-Activity Relationship, Thiophenes

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.


Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID22297109
PubMed Central IDPMC3528973
Grant ListR03MH084117 / MH / NIMH NIH HHS / United States
R03 MH084117 / MH / NIMH NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States
R01CA097061 / CA / NCI NIH HHS / United States
R01 CA161061 / CA / NCI NIH HHS / United States
R01 GM085081 / GM / NIGMS NIH HHS / United States
1 U54 HG005032-1 / HG / NHGRI NIH HHS / United States
R01 CA097061 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States