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Reflections on recent drug discovery trends
Recent trends in the drug discovery area have seen a variety of companies focusing on quality rather than quantity of compounds, instrumentation and data, which means the market demands high-quality compound synthesis for focused libraries; robust and easy-to-use compound storage; reliable transportation and compound handling across multiple sites; and information-rich assays such as those used for cell-based screening.
Automated combinatorial chemistry can now synthesize a near-infinite number of compounds. The problem is narrowing down the possibilities to a reasonable subset to synthesize and screen. Many off-the-shelf options exist for creating library subsets, but these are often limited in scope. Improved integration interfaces mean that multiple organizations now offer solutions that combine existing products to automate parts of a laboratory process. However, when processes change, existing products do not necessarily adapt and can be throughput limiting. Companies that provide custom automation and are able to develop technologies to fill gaps in the process are therefore seeing an increased demand for bespoke automation solutions. More flexible systems can be produced if the automation is tailored to the needs of the chemist, rather than the other way around, and throughput requirements can be built in from the start.
Once the required compound subsets have been synthesized, sample storage needs to be considered. This combines two fundamental issues: storage format (plate or tube) and maintaining sample integrity. Whilst there are many good automated storage solutions for plates, tubes or multiple formats, maintaining sample integrity during processing and long-term storage is still an issue.
Until recently, only large automated stores were available, such as systems from REMP and The Automation Partnership. These can require significant capital outlay, plus the expense of investing in custom built rooms and the equipment needed to maintain a suitable environment. Modular stores, such as TTP LabTech's comPOUND, are extremely popular because they are easy to expand, require less investment to set up and are self-contained, facilitating long-term frozen storage under an inert gas for increased sample protection. Some modular stores also offer the advantage of parallel processing, which can source samples from multiple stores at the same time. Thus, as new storage modules are added to increase the library size, sample throughput actually gets faster to keep pace.
Careful handling of precious stocks is also essential. Incorporating the latest liquid handling technologies into the drug discovery process has been vital to keeping pace with the demands for ever increasing throughput and miniaturized assay volumes to reduce costs. Systems must be designed to cope with the sheer number of assays and new chemical entities (NCEs) being developed. Furthermore, screening can be very costly as the testing of valuable compounds can result in substantial wastage. With this in mind, compound handling scientists should consider high-precision dispensers such as LabCyte's ECHO 555, TTP LabTech's mosquito HTS and Caliper Life Science's Sciclone inL10 workstation for reducing assay volumes and dead volumes from plate preparation.
Another valuable component in the early stages of drug discovery is high-content analysis (HCA), primarily due to its ability to resolve fluorescence assays temporally and spatially at sub-cellular resolution. This analytical capability differs significantly from conventional HTS readouts by reporting multiple fluorescence measurements on a per-cell basis rather than an average for each test well. In many instances, HCA also permits differentiation of sub-populations of cells within a given sample based on fluorescence, morphological and sub-cellular localization. Again, there are multiple technical options in this area including CCD imaging (e.g., Cellomics' ArrayScan VTI), flow cytometry (e.g., BD Biosciences' FACSAria) and microplate cytometry (e.g., TTP LabTech's Acumen eX3).
Amidst the new enabling screening technologies, cell-based approaches such as GFP- or RNAi-based technologies have emerged as being the most applicable for target validation and lead optimization, especially for intracellular therapeutic targets. HCA provides an unparalleled compound profiling ability across a vast range of cellular models. Given its accepted benefits, researchers are now seeking to expand the use of HCA into the HTS arena to increase drug discovery performance. Unfortunately, the marked increase in compound throughput required to achieve this goal does not merely involve replication of existing experimental workflows and instrumentation, but poses significant challenges for most existing technologies.
In short, the goal over the next 10 years will be to turn the existing 70 percent compound failure rate into a 70 percent success rate. Technologies are available to challenge this paradigm in the areas of focused compound synthesis, storage and handling of compounds and information-rich assays, however, these will continue to present both excitement and challenge for those engaged in the discovery of new drugs for some time to come.