Once a direction is chosen, it must be validated
scientifically, within a defined biological system.
Human disease or pathology is usually multifac-
torial, and the first task of the researcher is to
narrow down the search by defining the molecular
mechanisms better; optimally this will be a small
number of pathophysiologically observable pro-
cesses, for example the pinpointing of one or two
types of cells which are etiological.
From that cellular stage, the researcher next
defines specific molecular targets, such as receptors
on or specific isoenzymes in those cells, which
create the destructive phenotype. Is there an anom-
aly in a cell derived from a tumor, to use a cancer
example, which renders that tumor cell unique from
normal cells derived from the same tissue? If the
difference is significant and can be reproducibly
observed in the laboratory, it can be exploited for
drug discovery. In other diseases, the cell which is
identified can be normal but activated to a destruc-
tive state by stimulation with disease pathogens. In
rheumatoid arthritis, for example, the normal T-
lymphocyteisstimulatedtoreacttoantigenspresent
inthejoint,thusdevelopingadestructivephenotype.
The wider effects of inhibiting, modifying or
eliminating this new molecular target on the organ-
ism must also be considered. An enzyme that is
essential to life is a ‘no-hoper’ from the point of
view of the drug developer. The perfect target is
organ-, tissue- or cell-specific, thereby limiting
effects to the system involved in the disease. The
choice of a target for a disease will be critical to the
outcome and performance of the drug, and will
determine what organs or tissues will be suscepti-
ble to side effects. The ideal molecular drug target
is also one which is proprietary, whether having
been discovered in-house or in-licensed.
At this stage, an assessment is made as to
whether the medicine that could result is likely
to be palliative or ‘disease-modifying’. Disease-
modifying drugs (DMD) are those which directly
and beneficially deflect the natural history of the
disease. Nonsteroidal anti-inflammatory drugs
and methotrexate are examples of each of these
in patients with rheumatoid arthritis. Then prob-
ability of one or the other can alter economic
assessments of the research program, and lead to
a go-no-go decision in some cases.
Combining basic and applied research
Molecular targets are not always obvious, even
though cellular and histological disease patholo-
gies have been well described in the literature. At
this point, the researcher returns to the labora-
tory bench to design critical experiments (see
Figure 4.2).
The design and use of highly specific, monoclo-
nal antibodies (MAs) to proteins (or receptors)
derived from diseased tissue is a common approach
to probing for the correct molecular target. One
refinement of this approach is to use a variety of
these MAs to screen hybridoma supernatants for
activity in preventing a cellular manifestation of
the disease of interest. Taking cancer as an exam-
ple, malignant cells often contain over-expressed,
mutated or absent ‘oncogenes’ (i.e. genes which
code for particular proteins or receptors in normal
cells, but are mutated, and thus cause pathological
overactivity or underactivity of those gene pro-
ducts in tumor cells). Two well-known examples
of oncogenes are theRASandSRConcogenes,
which code for the production of RAS and SRC
proteins, respectively. Normal RAS protein regu-
lates cellular division and coordinates the nuclear
changes to alterations in the cellular architecture
required for mitosis (cytoskeleton and cell moti-
lity). Meanwhile, SRC protein is a key signaling
molecule which alters cell growth by modulating
the activation of theepidermal growthfactor (EGF)
receptor by its ligand. Many drug discovery efforts
have, therefore, targeted SRC, RAS, the EGF
receptor or any of their associated enzymes.
Thus, for example, RAS inhibitor discovery pro-
jects include prevention of the enzymatic event
which allows translocation of RAS from the cyto-
sol to the plasma membrane in cancer cells as one
way to prevent the effects of RAS.
Taking another example, consider the case of a
novel approach to treating inflammatory disease.
In 1997, a cell or molecular biologist beginning
such a research program might have found reports
in the literature of transgenic mice which, when
genetically engineered to cause monocytes to
express constant levels of the cytokine (TNF),
develop arthritis, as well as some of the early
clinical trials using anti-tumor necrosis factor4.2 DESIGNING A DRUG DISCOVERY PROJECT 45