Hauke Cornils and Stephen Hess, Evotec, Hamburg, Germany

The TRPM4 ion channel is a member of the Transient Receptor Potential Melastatin family, and is permeable to monovalent cations but impermeable to calcium. Deletion of this gene in mice ameliorates the course of disease progression in an animal model of MS. To find a specific inhibitor of TRPM4 channels to further define their role in MS, we screened a library of 250K small drug-like molecules using cells expressing human TRPM4 channels with a membrane potential dye readout.

Hits were confirmed and profiled for concentration-dependent activity at TRPM4, selectivity against TRPM5 and host HEK cells, and tested in Automated Patch Clamp assays.Recently, genetic approaches have increasingly impacted target identification, deconvolution and validation studies and thereby aid in the transition from phenotypic to target based drug discovery. Taken together, these case studies illustrate multiple successful approaches to hit finding with fit-for-purpose screening platforms.