Impedance-Based Measurement of GPCR Modulators in Drug Discovery – Characterization of Signalling Pathways in Recombinant and Non-Recombinant Cells

John Gatfield, Senior Lab Head Molecular Biology, Actelion Pharmaceuticals Ltd

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Launch presentation

About the speaker

Dr. John Gatfield studied and graduated in biochemistry at the University of Tuebingen/Germany and did his PhD thesis at the Basel Institute for Immunology/Basel/Switzerland with Prof. Jean Pieters on the cell biology of the host-pathogen interaction of tuberculosis bacteria with macrophages for which he received the Pfizer Prize in Infectiology 2001. Following a postdoctoral position at the Biozentrum in Basel he joined Actelion Pharmaceuticals Ltd as a lab head in the drug discovery department in 2003. He is a project leader of drug discovery programmes and strongly involved in cellular assay development and lead optimization in several additional projects.

Abstract

Idiosyncratic drug reactions (IDRs) are a major reason for withdrawal of drugs from the market. IDRs occur in 1/1000-1/10000 patients, making it impossible to pick up in preclinical or even Phase III clinical studies. Thus, the failures of drugs for IDRs reasons occur after they are released to the market, at great expense to the pharmaceutical company. Example: Trovafloxacin was introduced in 1997, when it quickly became the Company’s top seller, only to be black labeled in 1998, and ending up costing Pfizer $8.5B in lawsuits. While determining the underlying causes of IDRs is an active area of investigation, formation of reactive metabolites is hypothesized to play an important role in the development of unexpected toxicities of many compounds. A new assay is described that allows to monitor formation of reactive metabolites early in drug discovery before the clinical candidate is nominated. Discovery of such intermediates early allows drug discovery organizations to reduce the potential risks for development of IDRs later in the drug development process. Case studies will be shown on the application of the assay in drug discovery programs and the relative position of the assay in ADMET lead optimization and clinical candidate selection programs.

Launch presentation