Model Organisms in Drug Discovery

142 DROSOPHILA – A MODEL SYSTEM
in many cases RNAi does not completely inactivate gene function, thus
creating partial LOF phenotypes. Although these may be helpful by revealing
in which process the gene is most critical, interpretation of these phenotypes is
difficult without knowing the complete null phenotype. In summary, RNAi is
a useful and versatile method for the characterization of molecularly
characterized genes. As a gene discovery tool on a large scale (genomic or
subgenomic level) it is best used, given the variability of phenotypes, in the
context of genetically sensitized systems to search for novel components in a
given pathway. In this context it also serves as a suitable tool for target
validation in Drosophila.
5.3 Chemical genetics: lead identification in Drosophila
As outlined in the previous sections, genetic and reverse genetic approaches
are useful tools to identify or functionally validate drug targets. Whether these
are drugable, however, is another question. Genetics selects for function, not
drugability. If functionally relevant components of the disease-relevant
signaling pathway can be identified by mutational inactivation of the
corresponding gene, it should be possible to use this system to identify lowmolecular-weight
compounds that attenuate signaling by inhibiting the
function of the same essential component. This approach, termed ‘chemical
genetics’ by Schreiber (1998), relies on inhibitors to study the function of a
protein within a cell. In the pre-RNAi era of mammalian cell culture studies,
chemical genetics has contributed substantially to understanding the role of
various proteins, including various protein kinases. Success stories are
wortmannin, a PI3K inhibitor (Arcaro and Wymann, 1993), the MEK
inhibitor PD098059 (Alessi et al., 1995; Dudley et al., 1995) and the p38
inhibitor SB203580 (Lee et al., 1994; Cuenda et al., 1995), to name just a few.
Although wortmannin was first identified based on its inhibitory effect on the
respiratory burst of neutrophils and its target was identified subsequently,
both PD098059 and SB203580 were developed as specific inhibitors against
the corresponding kinases. In the following, we will discuss how Drosophila
can contribute to lead identification and characterization and we present an
example of how the combined use of chemical genetics and classical genetics
can provide targets and the corresponding leads.
Do leads that inhibit Drosophila proteins inhibit human proteins?
The usefulness of Drosophila as a lead discovery system depends obviously on
the probability that a compound that inhibits a Drosophila protein will also
inhibit its human homolog. Given the often relatively small degree of amino