Safety screening in early drug discovery: An optimized assay panel
Stefanie Bendels1, Caterina Bissantz1, Bernhard Fasching1
1Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland.
Journal of Pharmacological and Toxicological Methods
|July 9, 2019
Summary
This study developed a cost-effective, 50-target assay panel to identify off-target compound activity early in drug discovery. This optimized panel reduces safety-related failures and streamlines pre-clinical development by assessing compound promiscuity.
Area of Science:
- Pharmacology and Drug Discovery
- Computational Chemistry and Cheminformatics
- Toxicology and Safety Pharmacology
Background:
- Pharmaceutical development failure is often linked to adverse effects identified in pre-clinical and clinical studies.
- Early detection of off-target compound activity is crucial for reducing safety-related attrition during drug development.
- In vitro profiling of drug candidates against diverse targets is essential for compound selection, necessitating efficient poly-pharmacology assessment.
Purpose of the Study:
- To develop a cost-effective, optimized panel of 50 assays for assessing poly-pharmacology in early drug discovery.
- To enable the exploration of selectivity-focused structure-activity relationships for numerous drug candidates.
- To reduce the need for extensive in vivo testing by integrating in vitro screening data into compound selection.
Main Methods:
- A statistical-ranking approach was employed to select an optimized panel of 50 targets from 123 initial assays based on compound hit rates (IC50 ≤ 1 μM).
- Redundant targets were eliminated by prioritizing those with higher hit rates within compound groups.
- The selected panel was used to screen approximately 1200 compounds synthesized for Roche drug discovery programs at 10 μM.
Main Results:
- The optimized 50-assay panel effectively screened compounds, with 95% identified within the top 47-ranked assays.
- Adenosine A3 and 5HT2B receptors showed the highest hit rates (~30%) in the Roche panel screening.
- Integration of the panel hit score into compound selection for in vivo studies in an anti-infective program reduced mortality in mouse tolerability studies.
Conclusions:
- The 50-assay panel provides a cost-effective method for assessing compound promiscuity and identifying safety-relevant targets in early drug discovery.
- This panel has been routinely used at Roche to generate crucial safety and promiscuity data, informing pre-clinical development decisions.
- The panel's data successfully guided compound selection, leading to better tolerated molecules and reduced in vivo testing.
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