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May 15, 2011 (Vol. 31, No. 10)

Screening Innovations Proliferate

Newfound Ability to Perform Plate-Based Assays in Primary Cells Just One of the Practices Changing HTS

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    InSphero says its GravityPlus system facilitates the automated high-throughput production of 3-D microtissues. GravityPlus technology originates from the hanging-drop method, which allows for gentle gravity-driven microtissue formation at the liquid-air interface of small media droplets. By avoiding contact with any foreign material, it allows the cells to reform a tissue in a natural manner. The microfluidic design and surface engineering used for the plate reportedly assure consistent and rapid filling, stable drop formation, reliable media exchange, and supplementation of required supplements and/or cells.

    Screening technologies to advance drug discovery took center stage at the SBS meeting in Orlando at the end of March. Key themes emerging from the scientific sessions and evident in the new technologies and products on display in the exhibit hall included the need to develop more biologically relevant screening strategies, made possible in part by the increasing availability of novel 3-D cell constructs that more closely resemble in vivo tissue environments.

    Presenters shared their insights on recent advances and future directions in high-throughput screening (HTS) and assay development. Jonathan O’Connell, director of lead discovery and lead profiling at Bristol-Myers Squibb (BMS), traced the evolution of HTS at BMS and efforts to implement the most relevant bioassays.

    As HTS evolved in the early 2000s, the company added advanced compound storage and automated cherry-picking capabilities. BMS currently operates seven integrated, automated HTS platforms. By 2004, assay miniaturization was well under way, and a 384-well format was standard fare, allowing for screening of >500,000 compounds per campaign. Since about 2008, 1,536-well assays have become routine, enabled by precise, low-volume acoustic dispensing technology. A primary screen will now typically exceed one million compounds, at a cost of about $0.025/well.

    Secondary screening to assess compound selectivity and define mechanism of action commonly comprises at least four different types of assays and about 30,000 compounds. Improved integration of compound management/sampling and assay processing, with a more flexible infrastructure to support multiple assay technologies, is reducing cycle times and accelerating hit assessment and chemotype selection.

    The current driver in drug discovery is the therapeutic target, as “a lot of the easier targets have been done,” said O’Connell. More complex targets require more sophisticated and more varied types of assays: for example, assays performed in primary cells, stem cells, or in 3-D cell matrices; biochemical assays using full-length proteins, in the presence of other proteins or co-factors; multiplexing of reagents and compounds; high-content assays that generate multiple data points per well; GPCR assays that screen compounds, agonists, and other modulators in parallel; and phenotypic assays that utilize hit deconvolution to yield the desired outcome.

    O’Connell outlined three main challenges facing HTS. Noting that it is unrealistic to screen every compound in a library against every target, he encouraged companies to employ strategies such as CADD-based selection models to choose which compounds to screen. Additionally, better approaches are needed for screening ion-channel targets, to close the gap between conventional HTS assays and patch-clamp techniques.

    Furthermore, hit-seeking activities require more relevant models—primary cells and stem cells—and the ability to design more sensitive, miniaturized high-content assays at high throughput. Technologies that will help companies meet these challenges include high-content microscopy, high-throughput flow cytometry, high-throughput real-time PCR to measure changes in endogenous gene expression, cost-effective label-free assay platforms, high-throughput mass spectrometry, and microfluidics technology.

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