Drug discovery in reverse
Pathway visualization in Iconix's DrugMatrix.
Reversing the current drug-development path of 'target to drug to phenotype', chemogenomics, or chemical genomics, starts with a known drug that causes an interesting disease-relevant phenotype in vitro or in vivo, and then identifies the cellular target(s) for that drug. Chemogenomics is a powerful tool in target identification because you start with an active small molecule. By definition, any targets found are 'druggable' and are likely to be significant in the phenotype caused by the drug.
Seth Cohen, who recently moved from Millennium Pharmaceuticals to Caliper Life Sciences in Mountain View, California, likens chemogenomics to "reverse drug discovery". In other words, you take a drug compound with known effect and analyse in detail the result of exposure of the cell or organism to the compound. "This allows for a more precise understanding of the mechanism of action as well as potential causes of side effects. It also enables more intelligent subsequent screening of compounds with better, more relevant assay readouts," he says.
Iconix Pharmaceuticals in Mountain View, in collaboration with MDS Pharma Services of Lincoln, Nebraska, applies chemogenomics to the study of comprehensive responses of rats to treatment by a compound. Iconix uses CodeLink microarrays from Amersham Bioscience in Piscataway, New Jersey, which carry 10,000 probes for rat genes and expressed sequence tags, to measure gene expression in tissues from rats that have been treated with different drugs. MDS and Iconix have identified more than 250 clusters of genes whose expression changes in response to 600 drugs. "These clusters of genes, or 'drug signatures', describe and predict many specific mechanisms of action of the drug in the whole animal without the caveats of in vitro systems," says Pauline Gee, vice-president of predictive biology at MDS. Iconix's DrugMatrix database now includes more than 200 of these drug signatures, which are used by drug companies such as Bristol-Myers Squibb to help select candidate drug molecules more efficiently and to improve their understanding of the safety of new compounds before preclinical development.
Nature 428, 227 (11 March 2004); doi:10.1038/428227a
