The search for new drugs is getting increasingly more difficult. This is due to a variety of factors, but the main ones are: the ‘low hanging fruit’ has already been identified and the regulatory hurdles to overcome are becoming ever more numerous and becoming increasingly more difficult to pass. This has resulted in a high rate of attrition, with many candidates failing very late in clinical trials due to safety/toxicity concerns as opposed to lack of efficacy, incurring enormous financial losses. This resultant decrease in R&D productivity has placed the pharmaceutical industry under immense pressure to find better ways to bring new drugs to market. Of the drugs that are approved, many are follower drugs. This is in stark contrast to the real goal of drug research which is to identify a first in class molecule. As a result, strategies for screening to identify more and better lead compounds are constantly evolving.
Phenotypic screening has become ever more prevalent over the last decade, but their use with primary screening campaigns is not a trivial exercise. Key factors include the culture of large numbers of cells, their plating into microplates, and the complexity of the assay protocol being applied. Most high content imaging systems also offer limited capability for primary screening of full compound libraries due to their low throughput with high-density microplates, large data files and long image analysis times, making them impractical to deploy such systems for full deck library high-throughput screening. As a result when using this approach, a compromise is taken to screen only much smaller library subsets. Such a targeted approach reduces the power of using a phenotypic screen by limiting the chemical diversity being investigated.
Laser-scanning imagers, such as the acumen, combine the object-recognition capabilities of microscope based systems with the fast read speeds of bulk fluorescence readers (typically under 5 minutes per plate) which are compatible with primary full deck compound library screening campaigns. 96-, 384- and 1,536- well microplates can all be analysed at equivalent plate read times since imaging is performed on an area and not well basis. Here we discuss the requirements for a full deck phenotypic screen and describe how the acumen could be employed in a high-throughput, full deck phenotypic screen, with capacities up to over 300,000 wells/screening day.