It is estimated that a new drug can take up to 10 years to fully develop and test before it can be clinically approved, and some studies suggest it costs between $1 – 2bn USD to carry out this process. Unacceptable safety and poor efficacy are the leading cause of lead candidate attrition at all stages of drug development, however, those failing late in the process waste enormous sums of R&D time and investment. Attempts to reduce the number of efficacy and safety-related failures are being explored as the industry moves towards strategies that improve the physiological relevance of screening assays within HTS and identify potential toxicity earlier in the discovery process.
Here we demonstrate cellular assays which can be utilised early in the discovery process to identify potential safety and efficacy related issues sooner, thereby reducing overall development costs and improving failure rates.
cell health assays
Cell health (cytotoxicity) assays play a key role in the early drug discovery process as they study the effect of chemical substances and lead compounds on cells. The early identification of off-target drug effects results in more timely elimination of unsuitable lead compounds, which serves to reduce drug development costs.
Not only do cell health assays provide a crucial means of ranking novel compounds during screening but they are also routinely employed to gain a better understanding of changes at the cellular level in disease pathologies.
Cytotoxicity assays commonly employ a multiplexed approach to derive phenotypic and/or mechanism of action information from key cellular parameters such as plasma membrane integrity, DNA damage or synthesis, mitotic arrest, apoptosis, cell growth or motility. TTP Labtech’s acumen Cellista laser scanning cytometer is the ideal instrument for performing a wide range of multiplexed high-throughput cell-based cytotoxicity assays. Its ability to report data from each individual cell within each well (whole well imaging) in as little as 5 minutes/plate can offer data robustness and quality control advantages over field-based technologies when expecting cell loss from the microplate.
acumen Cellista offers data quality of phenotypic analysis, with the speed and simplicity of a plate reader at a 7 fold savings in cost.
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These assays include:
- live/dead – using standard dyes such as calcein-AM/PI or TOTO-3/TMRMThese combinations provide a more cost-effective approach to bulk read assays, such as CellTitre–Glo®, and offer the benefit of multiplexing with additional phenotypic assays to gain more high content data
- apoptosis – annexin V, Caspase-3, nuclear condensation
- genotox – phophohistone H3
With plate read and analysis times as low as 2 ½ minutes, regardless of plate format, acumen Cellista can be used for primary screening in the determination of off-target drug effects in the earliest phases of drug discovery. Fast scan times and easy to use Cellista software mean it is ideal for multi-user environments such as core screening laboratories.
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Peer reviewed publications bibliography:
- de Bruin, E. et al (2015). Genome-wide siRNA screen for anti-cancer drug resistance in adherent cell lines. Bio-protocol 5(10): e1474Calliss et al., A screening assay cascade to identify and characterize novel selective estrogen receptor downregulators (SERDs). J Biomol Screen
- Horman et al. Challenges and opportunities toward enabling phenotypic screening of complex and 3D cell models. Future Med. Chem.(2015) 7(4), 513–525
- Hodzic, J. (2015) A cell-based high-throughput screening assay for radiation susceptibility using automated cell counting. Radiation Oncology. February 27, 2015, 10:55
- Burl, S. (2013) Toxicity screens with increased insight: multiplex high-content imaging for studying compound performance.GEN 33 (18): 20-21
For a full list of available acumen Cellista publications click here.