Biomedical Engineering Reference
In-Depth Information
17
DIVERSITY-ORIENTED SYNTHESIS
AND DRUG DEVELOPMENT:
FACILITATING THE DISCOVERY OF
NOVEL PROBES AND THERAPEUTICS
JEREMY R. DUVALL, EAMON COMER, AND SIVARAMAN DANDAPANI
17.1
INTRODUCTION
As our basic understanding of the underlying biology in disease areas has evolved,
a fundamental challenge has emerged. New targets have been found that could hold
the key to a cure long sought. Despite the uncovering of a wealth of biological targets
in the genomic revolution [1], initial difficulties have instead led to the emergence
of a new term: undruggable . This generally refers to challenging targets, such as
protein-protein interactions (PPIs) and transcription factors, but ultimately is defined
as any target linked to a disease that we as an industry failed to disrupt by the use of
small molecules. As more challenging biological targets continue to emerge, small
molecules will have to evolve to deliver novel therapeutics.
A compelling case for this was presented by GlaxoSmithKline (GSK) in their
efforts to discover novel antibiotics [2]. As resistance emerges in different bacte-
rial strains, the drug discovery industry has had limited success countering, with
20 antibiotics coming onto the market since 2000, most of which are derivatives of
existing antibiotics and have known liabilities such as toxicity or resistance [3]. This
is not due to a lack of trying, although with such limited success, many pharmaceu-
tical companies are now leaving the field. GSK's effort focused on high-throughput-
screening (HTS) campaigns against targets that had emerged from the sequencing
 
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