Model Organisms in Drug Discovery

3. A hit identifies a biologically active compound in a disease model but not
directly its target. For further development it is therefore mandatory to
have the right tools to identify the corresponding target (see later section on
mechanism-of-action studies). For instance, the activity of a compound
within a pathway can be narrowed down by testing its activity in different
genetic backgrounds, or by the identification of resistance mutations by
genetic screening.
In summary, considering the advantages and disadvantages of drug testing
in Drosophila, INVOSCREEN TM is a powerful tool to screen for biologically
active compounds for complex traits. It is most effectively used in combination
with genetic screens because this increases the chance of identifying the golden
triplet: the target, its lead and their function.
Search for compounds inhibiting cellular growth
Cellular growth is a prerequisite for tumor growth and involves more than just
the control of the cell cycle machinery (Neufeld et al., 1998; Stocker and
Hafen, 2000). The elucidation of mechanisms underlying growth control will
provide insight into the way to interfere with tumor growth, therefore one of
the goals of The Genetics Company, Inc. is to identify the genes essential for
cellular growth in Drosophila and to develop low-molecular-weight inhibitors
against the corresponding proteins. For this purpose, in parallel to the
genome-wide saturation screen for genes involved in cell and organ growth
(see earlier section on screens for recessive mutations), we are performing a
chemical genetic screen for compounds that inhibit cellular growth. The
feasibility of this approach was demonstrated by the striking similarity of the
phenotype obtained by genetic mutations of dTOR and dPI3K and the effects
of the administration of the corresponding chemical inhibitors rapamycin and
wortmannin (Stewart et al., 1996; Weinkove et al., 1999; Oldham et al., 2000;
Zhang et al., 2000; H. Stocker, unpublished; Figure 5.5). It is worth noting
that rapamycin, which has been used successfully as an immunosuppressant, is
now also in clinical trials as an anticancer drug and for other cell-growthrelated
disorders such as restinosis (Hidalgo and Rowinsky, 2000).
Mechanism-of-action studies
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For many drugs currently on the market the corresponding target is not
known. Drosophila can be used to identify the target and the mechanism of
action (MOA) of such drugs. Of course, the drug in question has to produce a
specific, clearly detectable phenotype in Drosophila and this phenotype must
be related to the action of the drug in humans. In many cases, the observed