Development of new compounds to define the potential of TRPM4 inhibition for prevention and suppression of Ca2+ dependent cardiac arrhythmias.

• Applicants: Professor Dr. Marc Freichel; Professor Dr. Manuel A. Friese; Professor Dr. Christian Klein
• Subject Area: Pharmacology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531047917

Ca2+ dependent arrhythmias are a critical feature of conditions such as CPVT, ischemia and atrialfibrillation. TRPM4 is a Ca activated cation channel and an interesting drug target for the preventionand suppression of this type of arrhythmias. To date, the only in vivo applicable blockers of TRPM4are meclofenamate and glibenclamide, which have obviously other prominent targets and have arelatively low efficacy to block TRPM4. Therefore, we aim to design a new class of high-affinityTRPM4 blockers, and determine the role of TRPM4 in tissue with high-translational value. Specifically,we aim to: i) to define the binding site for meclofenamate by CryoEM, in order to delineate thebinding pocket for inhibitors on the TRPM4 protein. Based on this information we will create an insilico model that will be used to ii) identify new compounds with high affinity using a ultra-large scalevirtual screen and structure-activity relation optimisation of meclofenamate through medicinalchemistry, and iii) test the effect of novel compounds and meclofenamate in human iPSC derivedcardiomyocytes , and in living guinea pigs. Taken together, this project will deliver new insight in themechanism of block of TRPM4, and the translational potential of TRPM4 targeting as a strategy toprevent cardiac arrhythmias.

• DFG Programme: Research Grants
• International Connection: Belgium
• Cooperation Partner: Professor Rudi Vennekens, Ph.D.