Multiplexed biosensors for identifying and monitoring cellular events associated with drugs therapeutic efficacies and side effects
Overview
Development of new biosensors and bioinformatic tools to dissect the multiple signalling pathways engaged by G protein coupled receptors (GPCRs) in response to ligand binding. This will help to establish the signalling signature to predict drug activity and side effects.
G-protein coupled receptor (GPCR) ligands account for an appreciable percentage of drugs on the market. However, their multiple efficacies in the regulation of distinct signalling pathways have only recently been recognized as important for the development of drugs with better therapeutic and safety profiles. This multidisciplinary project aims at developing panels of 20 to 30 genetically encoded biosensors to simultaneously monitor primary signalling pathways engaged by GPCRs. These arrays will generate universal drug candidate profiling tools based on bioluminescence resonance energy transfer (BRET) technology, which is very well suited for both high-throughput screening and low-throughput validation. A signature will be established as a first correlation between distinct signalling modalities and both the therapeutic efficacy and the side effects of beta-blockers. Predictions made from these studies will then be tested in ex vivo and in vivo pre-clinical models to confirm the utility of a comprehensive signalling signature to develop drugs with improved efficacy profiles and fewer side effects. The team has successfully generated, optimized and validated a large number of useful biosensors. Through the mentorship program, CQDM’s pharma sponsors have demonstrated a high interest for some of the biosensors developed. Some of them are already being transferred for evaluation to the pharma partners R&D centres.
Impact on the drug discovery process
- Create technological and methodological tools to monitor the complexity of ligand signaling efficacy in early steps of candidate drug screening and profiling.
- Bring more effective medicines to the clinic by establishing better correlations between the desired therapeutic efficacy and the cellular activities of therapeutic targets.
- Reduce development risks by introducing better predictors of efficacy and undesired effects earlier in the R&D process.
Key facts
- The first GPCR was identified 27 years ago. To date, more than 300 different druggable GPCRs have been identified among which 46 have been successfully targeted by a drug
- Approximately 40% of currently marketed drugs target GPCRs. Notable examples include Claritin® (allergies), Prozac® (depression), Vasotec (hypertension) and Serevent® (asthma)
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