Model Organisms in Drug Discovery

160 MECHANISM OF ACTION IN MODEL ORGANISMS
Figure 6.1 Mechanism of action process flow. First, animals are treated with compounds
and analyzed for phenotypes. Once a robust compound-induced phenotype is identified,
genetic modifiers (resistant or hypersensitive) of the compound are sought by a forward
genetic screen (i.e. chemical mutagenesis), a reverse genetic screen (i.e. RNAi collection)
and/or a candidate gene approach. In the forward genetic screen, mutations are mapped to
a chromosome location and the mutated gene is identified. In the reverse genetic screen, the
gene is known at the starting point. In the candidate gene approach, the starting phenotype
hints at potential candidates that are tested directly (see text for details)
The more precise and well characterized the phenotype, the better the
hypothesis. When an effect is observed from compound administration, then
one can ask if the effect mimics that of a specific gene disruption phenotype.
Often the phenotypic effect of a compound suggests a well-known signaling
pathway that is being disrupted. This comparison is possible because the
specific effect of individually removing many genes from C. elegans or
Drosophila has been studied intensively, and because, in many cases, these
genes have been integrated into pathways and genetic circuits. Follow-up
experiments include the testing of sentinel strains that are compromised for