12.10.2021 - Transporters in Drug Screening and Toxicity Testing
Transport proteins and pumps are getting more established as drug targets. However, the set of available technologies for screening and hit validation is lean. In session four of the Transporter Webinar Series we hear from experts in the pharma field how SSM-based electrophysiology can support transporter drug screening as a potent tool.
Title: SSM-Based Technology for Screening of Transporter Modulating Compounds – a Case Study
Thomas Licher, Head of Integrated Drug Discovery
The solid supported membrane (SSM)-based electrophysiology is a sensitive, membrane-based method for transporter analysis, and current technical developments target the demand for automated, accelerated, and sensitive assays for transporter-directed compound screening.
In this webinar we want to show the development of a specific SSM-based assay for the electrogenic amino acid transporter B0AT1 (SLC6A19) and in addition the suitability of this technique for pharmacological compound identification and optimization. B0AT1-dependent currents were successfully inhibited using an established in-house tool compound. Evaluation of current stability and data reproducibility verified the robustness and reliability of the applied assay. Active compounds from primary screens of large compound libraries were validated, and false-positive hits were identified. These results clearly demonstrate the suitability of the SSM-based technique as a direct electrophysiological method for rapid and automated identification of small molecules that can inhibit B0AT1 activity.
This technology is also heavily used in the Resolute transporter consortium and a summary of this efforts will conclude the webinar.
Title: SURFE2R-Based Assays for Mitochondrial Toxicity Screening and Intestinal Transporter-Mediated Drug Delivery
Roberta Benedetto, Scientist
Transport proteins are important targets but also anti-targets in Drug Discovery. Electrogenic transport can be directly monitored using SSM electrophysiology. With the decent throughput of the SURFE2R™ platform, this assay technology supports screening applications for lead assessment and optimization. Here, we show two examples:
1) Compound toxicity through interference with the mitochondrial respiratory chain and
2) Transport of pro-drugs/peptidomimetic compounds through the epithelium via PepT1.
To be conclusive, such applications typically require compound titrations. SSM chips only support a limited number of measurements or can fail completely. Hence, data quality may be insufficient if titrations are performed in a single well. On the other hand, the cost of cross-well titrations may be prohibitive. Assay.Works developed a hybrid titration scheme ("IXwell concentration-response") combining an economic number of wells per compound with robustness against chip failure.
When: Thursday October 12th, 4 PM CEST, 10 AM EDT
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