Screening, Profiling and Analytical Facility (SPAF)
The NCCR TransCure screening facility provides the manpower, expertise and equipment required to develop and validate screening assays for diverse transporter targets. We help the PIs from the individual projects to upscale their assays in order to use them to evaluate small molecules in a typical medium-throughput format (<6’000 compounds) for primary target activity, and if required for selectivity studies. Compounds are provided from the chemistry groups either as targeted sets selected by virtual screening, from CROs, or as series of focused synthetic compounds generated in house or in collaboration with industry partners. Current project with links to the screening facility are LAT1, DMT1, endocannabinoid transport, OATP and TRPM4. In-house facilities for screening include basic 96-well robotics for compound handling if required; a FLIPR automated 96-well parallel fluorescence plate reader, plate washers, and a TopCount NXT 96-well scintillation counter. We collaborate with Novartis for high-throughput screening (HTS). Our chemical tools and probes are fundamental to study biological phenomena. For instance, extensive screening initiatives have led to the optimization of TRPV6 calcium channel inhibitors and TRPM4 sodium channel inhibitors by using a 3D ligand-based virtual screening method. In order to address analytical problems for the in vivo proof of concept, we employ LC-MS/MS (Sciex 4000 and 5500) to quantify tool compounds in vivo and to perform pharmacokinetic experiments. A future focus of the SPA is to engage in translational research. In collaboration with PD Dr. Reto Kaderli (Inselspital Bern), Dr. Martin Lochner (IBMM) and Novartis, we are exploring tools to target calcium-sensing receptors (CaSR) in the parathyroid gland.
Ozhathil LC, Delalande C, Bianchi B, Nemeth G, Kappel S, Thomet U, Ross-Kaschitza D, Simonin C, Rubin M, Gertsch J, Lochner M, Peinelt C, Reymond JL, Abriel H. (2018), Identification of potent and selective small molecule inhibitors of the cation channel TRPM4. Br J Pharmacol.175(12):2504-2519.
Simonin C, Awale M, Brand M, van Deursen R, Schwartz J, Fine M, Kovacs G, Häfliger P, Gyimesi G, Sithampari A, Charles RP, Hediger MA, Reymond JL. (2015) Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method. Angew Chem Int Ed Engl., doi: 10.1002/anie.201507320.