A Revolution in R&D

CHEMICAL GENOMICS—FORWARD OR REVERSE
When companies say they are pursuing chemical
genomics, they are usually referring to large-scale
reverse chemical genetics. (That is how the term is
used in our report.) This approach involves finding
chemical compounds that bind to a known target.
Companies often perform this task for entire target
classes; it is especially popular for protein classes
that are known to be highly drugable, such as Gprotein
coupled receptors (GPCRs). The assay for
binding does not need to provide functional information
relevant to a specific disease state—biological
function can be assessed in validation experiments.
The alternative is forward chemical genetics. This
approach begins with functional knowledge. A
library of compounds is screened in an assay that
tests for changes in a specific biological function.
One immediate result would be to process the glut
of identified targets more quickly: instead of joining
the logjam at the validation stage, a great many
of them can now be diverted directly to screening.
If they fail there, they can be discarded right away,
and thus simply bypass most of the validation stage
altogether. In other words, screening moves up the
value chain to rest alongside validation, in a parallel
rather than consecutive position. By bracketing
the industrialized steps of target identification and
chemical screening, chemical genomics has given
the value chain a remarkable makeover.
The key is to move lengthy, messy biology far downstream
where you know it’s worth pursuing. Many
targets aren’t drugable, so just validate the smaller
drugable subset.
—SVP of discovery,
leading biotech company
The effect of this new value chain is dramatic: time
to drug is cut by a further two years (that’s on top
of the year already saved by using genomic target
identification). On the other hand, there is a large
3. In July 2001, Aurora Biosciences was acquired by Vertex Pharmaceuticals.
The intention is to screen a library against all expressed
genes in the system under investigation.
This approach has the tremendous advantage of allowing
the identification of targets without any presumptions
as to their function. Additionally, these
targets can help to elucidate the mechanism of disease,
thereby revealing other potential targets in relevant
pathways. The drawback is that forward chemical
genetics has not yet been industrialized, and
throughput levels are therefore very low. According
to our model, implementing it today would increase
costs to more than $1 billion per drug, owing to the
use of “slow” biology, which is needed to set up the
screening assays in chemistry. The expert estimate is
that forward chemical genetics is still as much as
five years away from being economically feasible.
increase in cost, offsetting all cost savings from target
identification. But the tradeoff is still positive.
In a highly competitive market, where new entrants
are continuously eroding share, chemical genomics
can add more than $200 million in value per drug.
(In less competitive conditions, the value added
may be as little as $20 million.)
No doubt chemical genomics costs more—but you
take the loss to gain the speed. Time is money.
—SVP of discovery and technology,
major pharmaceutical company
One important drawback of chemical genomics is
this: it is limited mainly to known target classes.
With targets of unknown function, results become
very difficult to interpret. The proxy assays used for
screening—heat-stability assays, for instance—tend
to yield both false positives and false negatives.
Nevertheless, chemical genomics is already being
pursued throughout the industry. Several big pharmaceutical
companies have adopted it, and genomics
companies such as Aurora Biosciences 3 and
15