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Selecting ‘true’ hit compounds, with drug-like mode-of-action is a major challenge when evaluating the hits from ultra High Throughput Screening campaigns. Owing to the possibility of undesired compound-assay interference, it is crucial to have appropriate follow-up assay cascades in place for any successful hit finding effort. Our in-depth knowledge in designing a hit triaging cascade ensures the identification of high-quality starting points for future medicines. We design cascades for different readout technologies and target classes, proprietary chemical biology approach with ‘Robustness Set’ compound collection along with cheminformatics capabilities.
This is a major challenge in evaluating hits from HTS campaigns! It is widely accepted that besides the quality of the library and the primary assay, the success of any uHTS campaign is largely dependent on the post-screen hit-triaging phase, particularly because of undesired compound-assay interference leading to false-positive data. The undesired false-positive effects of these compounds disturb the hit selection process, thus requiring orthogonal assay readouts and adjustments in the primary assay conditions. Such false positives could be generally categorized into technical false-positives (e.g. quenchers, auto-fluorescence, inhibitors of secondary enzymatic reactions) and hits with undesired modes-of-action (chelators, aggregators, redox, etc.). Thus, a comprehensive hit triaging cascade of assays including counter-screening, deselection, orthogonal, selectivity as well as target engagement biophysical assays are required.
To dissect such liabilities early in the assay development phase, the “robustness set” compound collection was established together with the University of Dundee, Newhouse. The robustness set exists of selected molecules from the literature with well-defined assay interfering properties and so-called clean compounds for which we do not expect assay interference. These were supplemented with many DMSO controls, all in a ready-to-employ single 1536-well plate. The application of the robustness set not only provides a framework to identify assay liabilities and tailor uHTS assay conditions such that minimal interferences occur but also helps to design suitable follow-up assay cascades for successful hit triaging.
Percentage of active compounds per class
Percentage of active compounds per class
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Pivot Park – Banting Building (RE2423)
Kloosterstraat 9
5349 AB Oss
The Netherlands
Pivot Park Screening Centre
Building OP
Kloosterstraat 9
5349 AB Oss
The Netherlands
