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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

A Chemical Genetics Approach for the Discovery of Apoptosis Inducers: From Phenotypic Cell Based HTS Assay and Structure-Activity Relationship Studies, to Identification of Potential Anticancer Agents and Molecular Targets.

The approach of chemical genetics has been widely used to study biological systems and to discover new drugs, signaling pathways and targets. The current review focuses on the development and utilization of a cell- and caspase-based apoptosis induction assay for the discovery of apoptosis inducers. We began with the development of a cell based phenotypic assay, which was used for the identification of small molecules that exhibit apoptosis inducing activities, including N-phenyl nicotinamides, gambogic acid, indole-2-carboxylic acid benzylidene-hydrazides, 4-aryl-4H-chromenes and 3-aryl-5-aryl-1,2,4-oxadiazoles. Through medicinal chemistry and biological studies, in vivo active compounds were identified, such as MX116407 as a tumor vascular disrupting agent with potent in vivo anticancer activity. The molecular targets of in vivo active compounds were identified using reagents designed and synthesized based on the SAR, including the identification of tail-interacting protein 47 (TIP47), an insulin-like growth factor II (IGF II) receptor binding protein, as the molecular target of 3-aryl-5-aryl-1,2,4-oxadiazoles; and Transferrin receptor I (TfR), a transmembrane protein that interacts with transferrin (Tf) for the transport of iron into cells, as the molecular target of gambogic acid. We demonstrated that chemical genetics is a very useful approach for anticancer drug research, from the discovery of potential drugs, to the understanding of signaling pathways and identification of druggable targets.[1]


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