Model Organisms in Drug Discovery

98 DROSOPHILA AS A TOOL FOR DRUG DISCOVERY
delaying larval development may be halved if using flies heterozygous for a
null mutation in the rapamycin target gene dTOR, or in the S6K gene, which
is the downstream target of dTOR (Britton and Edgar, 1998). Also, the 2 mM
histone deacetylase inhibitor SAHA was able to suppress, by 40%, the adult
lethality caused by neuronal overexpression of the polyglutamine repeats in
the Huntington’s disease gene (Steffan et al., 2001).
Chemical genetics
The use of Drosophila for compound screens is not limited to the goals of hitto-lead
programs. Compounds can be used as chemical tools for understanding
the biology of disease pathways. This approach has been used for
quite a long time in biology, especially in the field of neurobiology. For
example, the scorpion charybdotoxin has been used extensively for the
characterization of potassium channels (MacKinnon et al., 1998). Recently,
this strategy has been formalized as ‘chemical genetics’ (Mitchison, 1994;
Crews and Splittgerber, 1999; Stockwell, 2000). The chemical structures of hit
compounds from a large diversity screen may tell us what kinds of target
molecules they hit in the pathways, based on compound–target knowledge
databases. Alternatively, based on the concept that ‘similar folds bind to
similar ligands’ (Breinbauer et al., 2002), screens may be done using special
compound libraries targeted to conserved protein domains/fold structures,
such as the metallopeptidase and tyrosine kinase domains. This approach may
provide information for an educated guess about the candidate genes of a
disease pathway and provide impetus to initiate a genetic screen or test to look
for those druggable target genes.
Pathway-targeted compound screens also should be done using Drosophilacultured
cells. This is because the same assay readout of a pathway in a cell line
can be used for both compound screens and dsRNAi-based genetic screens. The
integration of information from both types of screens will generate a compound–
target pair hypothesis that can be tested rapidly using the same cellular assay –
transgenic Drosophila – and equivalent assays in mammalian cells.
In summary, through careful evaluation, good experimental designs,
technology improvement and integration of information from genetic screens,
a Drosophila-based compound screen has the potential of adding significant
value to the drug discovery process.
Using Drosophila for evaluating the genetic toxicity of drugs
Before a new drug goes to clinical trials its toxicity profiles must be determined
to ensure the safety of patients. One potential toxic property of a drug is its