What to Test, When and How

Genotoxicity data should become an important part of a compound s profile and can provide value in decision making at all stages in discovery from libraries containing millions of compounds to leads progressing to candidate selection. Each is here considered in turn. 

None of the genotoxicity assays described here have been used for whole large libraries, as none have sufficient throughput. This is not least because most assay developers do not have access to the instrumentation required for developing HTS or ultra-HTS methods. The only feasible approach would be to adopt a progressive longer-term strategy, and collect the data over a period of a year or more. 

The first level of genotoxicity testing likely to be used in the near future is hit profiling. For numerical reasons, hits from a discovery campaign can be considered alongside smaller complete libraries of natural products and specialist collections enriched for particular target types (inhibitors of kinases, proteases, HDACs, etc.). All would benefit from the early inclusion of genotoxicity data in the profile. Of the assays 

A combination of two tests is clearly better than one, but at this early stage, when there is still more chemical development likely, one is probably enough. Given that in silico methods are most effective in the identification or designing out of Ames positive compounds, a single eukaryotic screening test would probably be optimum. 

1 Aubrecht, J., Osowski, J.J., Persaud, P., Cheung, J.R., Ackerman, J., Lopes, S.H. and Ku, W.W. (2007) Bioluminescent Salmonella reverse mutation assay a screen for detecting mutagenicity with high throughput attributes. Mutagenesis, 22, 335-342. 

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