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

Abstract

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.

• Authors: Michel Weïwer, Joshua A Bittker, Timothy A Lewis, Kenichi Shimada, Wan Seok Yang, Lawrence MacPherson, Sivaraman Dandapani, Michelle Palmer, Brent R Stockwell, Stuart L Schreiber, Benito Munoz
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 4 Pg. 1822-6 (Feb 15 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22297109 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Small Molecule Libraries
• Thiophenes
• HRAS protein, human
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Fibroblasts
• Humans
• Inhibitory Concentration 50
• Molecular Structure
• Mutation
• Proto-Oncogene Proteins p21(ras) (antagonists & inhibitors, genetics, metabolism)
• Rats
• Small Molecule Libraries (pharmacology)
• Structure-Activity Relationship
• Thiophenes (chemistry, pharmacology)