Emerging Safety Science Workshop Summary (2008) / Chapter Skim
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3 Screening Technologies I: Human Cell–Based Approaches
3 Screening Technologies I: Human Cell–Based Approaches
Pages 13-27
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From page 13... ...
The first topic in this series was emerging screening technologies that are based on human cells. The ideal screen Dr.
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From page 14... ...
System Overview Although BioMAP uses an artificial cell culture system, it is based on human cells placed in complex environments designed to reflect key aspects of the natural environments the cells would experience in the human body. Using information from the literature, the company's scientists strive to create environments that mirror real situations in which multiple pathways are active at the same time -- pathways similar to those believed to work together in different disease states.
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From page 15... ...
To create these complex environments, the BioMAP system combines a number of cells, sometimes of a single type and sometimes a defined mixture, such as peripheral blood mononuclear and endothelial cells. The purpose of using multiple cells is to capture cell–cell interactions and begin to model at a simple level what is going on at the tissue level.
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From page 16... ...
This broad range of applications is not surprising because even though these four cell systems were created to model inflammatory and cardiovascular states, the cells they contain express the receptors that cancer cells adapt and use for their own purposes, as well as many of the receptors involved in controlling metabolism and lipid biology. The resulting breadth of coverage of targets and pathways provides BioSeek with a unique opportunity to assess effects across a broad array of human biology in a common format.
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From page 17... ...
Because these assays are performed by ELISA using robotics, it is possible to test hundreds of compounds in multiple assays each week, to repeat the tests a number of times, and therefore to collect enough data that the statistical analysis can be quite sophisticated. These statistics allow the researchers to calculate a 99 percent significance envelope, which is indicated in the figure by a gray background; anything outside of this envelope is a highly significant response.
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From page 18... ...
These data demonstrate that BioMAP activity profiles are robust and reproducible, and that the profiles retain their shape across multiple drug concentra Landscape view tions. The shape of a drug's BioMAP profile thus provides a fingerprint or signature for its biological function and target.
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From page 19... ...
However, the next dozen hits were other p38 MAP kinase inhibitors. This example demonstrates that analysis of the BioMAP profiles makes it possible to rapidly link chemistry to biology and identify mechanisms of action.
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From page 20... ...
p38 kinase Mechanism of Action Secondary Activities Compounds with the same Compounds with different target (mechanism of targets or strong action) cluster together secondary activities do not cluster together nuclear hormone receptors of the PPAR family, a result that would have been immediately apparent from BioMAP analyses.
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From page 21... ...
The system focuses on molecules, selected for their information content, that mediate disease, are sensitive to many targets, have high predictive value, and have potential suitability as clinical biomarkers. Butcher described BioSeek's goal of developing a comprehensive BioMAP database connecting drug biology to clinical responses.
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From page 22... ...
To better understand these mechanisms, Odyssey Thera developed a method for observing the actions of drugs in the context of living human cells. High-Content Chemical Biology The profiling method developed by Odyssey Thera relies on two main techniques.
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From page 23... ...
The company's assays now encompass a wide variety of targets in the cell: GPCRs, kinases, cytoskeletal proteins, GTPases, G proteins, transcription factors such as p53, and nuclear receptors such as PPARγ, as well as some less common targets such as protein ubiquitination and the proteasome. The assays can also be used to look at apoptotic machinery, heat shock proteins, ion channels, and protein complexes involved in chromatin remodeling.
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From page 24... ...
It is simple to use the underlying data to understand the effect of a specific chemical substitution on a compound's activity within the cellular networks. Application to Safety Science Application of this technology for safety and toxicology analysis of new compounds requires the generation of fingerprints or signatures for toxicants as well as for efficacious drugs.
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From page 25... ...
Changes in signal intensity or location for compound versus vehicle control are represented by a color code, where green represents an increase and red a decrease in PCA signal versus control in units of coefficient of variation of each assay. Data are clustered by compounds and assays to identify on-pathway or off-pathway effects of compounds on specific pathways.
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From page 26... ...
Using this technology, an average profile for all statins across the whole assay panel can be created, and then various drugs in the database can be compared with this average profile. While most of the statins tested resemble this average profile, pravastatin deviates notably from the average.
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From page 27... ...
Odyssey Thera's current strategy is to rigorously define training sets based on toxicants as well as desirable drug classes and then to match test compounds to these profiles. In this way, the researchers hope to be able to enable a deeper understanding of cellular networks and drug targets and to facilitate more informed discovery and development decisions.
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