Biology Reference
In-Depth Information
each packed with biological meaning. Once combined
with an automated platform technology, SGA led to the
first ever genome-scale di-genetic interaction map,
providing a comprehensive view of the 'genetic landscape
of the cell' [27] (see Chapter 6).
refuse and was quickly embraced. The advances in tech-
nologythereforeledto(andinfactdemanded)anew
paradigm to justify the research and infrastructure
investments that included large teams of chemists, auto-
mation engineers, and assay specialists to achieve this
industrialization of drug discovery. The atmosphere was
one of optimism and great promise, and from this frame
of reference the modern discovery paradigm was born. In
hindsight, the rush to embrace the target-oriented para-
digm may have been premature, as little biological
support could be provided to prove that the assumptions
of the paradigm are valid and effective. At the same time,
drug discovery invested heavily in genomics, and pursued
many 'thinly' validated genomic targets, despite lacking
a clear disease relevance. In a short time, mountains of
data were produced by HTS, and the drive for ever faster
and cheaper throughput became the central focus, fueled
by the 'biotech boom' of the 1990s. By the end of the
decade, however, despite the three orders of magnitude
increase in HTS throughput, the return on the massive
investment was a disappointment, as few new therapies
had been discovered.
Thus the decade enthralled by technological advances
ended with greater efforts being expended for diminishing
returns, a result due in large part to incomplete knowledge
of the underlying physiology and biology. One of the
potential solutions to reversing this trend has been
a renewed focus on academic discoveries and a fostering
of public
Drug Behavior is Promiscuous
Modern Drug Discovery: A Historical
Perspective
The foundation of modern drug discovery rests on the
paradigm of the early 1990s; that a small molecule with
demonstrated ability to bind to/inhibit the activity of
a target protein with high affinity/high potency in an in vitro
biochemical assay will translate into an effective low-dose
therapy. Traditionally, the potency of a small molecule
measured in an in vitro binding or biochemical assay served
as accepted evidence of the in vivo mechanism of action
(MOA). In retrospect, given our current understanding of
biology, the assumption that the in vitro behavior of a small
molecule would exhibit the same behavior once in the in
vivo context of the complex environment of a cell, let alone
a human patient, seems improbable at best. How the MDD
paradigm emerged and, moreover, was passionately sup-
ported from the early 1990s to the present day is thus a bit
of a mystery, one best understood in its historical context.
Prior to ~1980 the discovery of new drugs was largely
a result of careful pharmacology combined with seren-
dipity and a heavy reliance on the isolation of natural
products associated with long histories in traditional
medicine. As advances in synthetic chemistry developed,
the focus on developing improvements in compound
isolation techniques shifted towards modifying existing
drugs or natural products to improve their therapeutic
value. Powerful bioactive molecules were also discovered
in humans (e.g., hormones) during this period, and many
were successfully modified to become drugs; thus the
potent effects of small molecules had been realized. In the
early 1990s, several advances in technology coalesced
nearly overnight, and ushered in the era known as the
high-throughput screening (HTS) revolution. Key to this
revolution were (1) the discovery of recombinant DNA
genetic engineering technologies, allowing large amounts
of proteins to be produced in vitro; (2) improvements in
chemical synthesis and combinatorial chemistry; and (3)
the increased miniaturization, speed and liquid handling in
robotic automation.
Together, these technological advances offered the
pharmaceutical industry access to a vast number of novel
compounds to explore new chemical space, and to
increase the current screening throughput capacity by
orders of magnitude (~1000 screens/day to 100 000
private partnerships. In order for this approach
to succeed, it is essential that (1) the successful strategies
of pre-genomic drug discovery be reclaimed; (2) the
mistakes of the HTS revolution are not repeated; and (3)
the right technologies are used for the right applications.
Today, new technologies continue to improve the effi-
ciency and robustness of mining omic data for drug
discovery opportunities, but to be effective they must be
appropriately focused. To avoid the disconnect that
occurred as a result of the assumption that increased data
quantity
e
more new therapies, technologies must be
actively and realistically evaluated for their ability to
provide meaningful biological
¼
insight, and adjustments
made in real time as needed.
Because of the dominating influence of target-oriented
approaches to MDD over the last 20 years, it is not
surprising that even well-established drugs are currently
poorly characterized in vivo. The MOA of these older drugs
must be revisited using in vivo approaches to understand
their behavior. Indeed, several efforts that aim to repurpose
older, already approved drugs require such approaches in
order to illuminate new MOAs. Comprehensive character-
ization of MOA in vivo is difficult, and full understanding of
in vivo MOA can, in theory, only be achieved by testing
a small molecule for its ability to inhibit every protein
activity in the cell. Such methods are currently unfeasible in
þ
screens/day). This opportunity proved too tempting to
Search WWH ::




Custom Search