Functional characterization of the inhibitory effect of Phenhydan® in the course of regulated necrosis

• Applicant: Professor Dr. Stefan Krautwald
• Subject Area: Nephrology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 400339789

In the last decade, the scientific realization that, like apoptosis, necrosis also follows a genetically defined pathway has fundamentally changed the general understanding of cell death. Regulated necrosis plays a central role in diseases including cardiac infarction, stroke, sepsis and cancer. The individual signal transduction pathways of numerous modalities of regulated necrosis have been deciphered in increasing detail. However, regrettably, not one inhibitor of regulated necrosis has been approved as a therapeutic drug that is routinely used in the treatment of the aforementioned diseases in the clinic. Because the hydantoin derivative necrostatin-1 is the most effective and widely used inhibitor of necroptosis, we have examined numerous hydantoin derivatives that are already successfully used as licensed drugs in ordinary clinical routine, regardless of their normal areas of application, merely considering their inhibitory effect in necroptotic-mediated cell death processes. In our preliminary work, the drug Phenhydan® (active substance phenytoin), which is currently used for the treatment of epilepsy, was a highly effective inhibitor of necroptosis.We wish to examine the effect and efficiency of Phenhydan® in the course of pathophysiological cell death processes in a clinical phase IIA study. To facilitate this, the proposed project aims to identify the presently unknown intracellular target(s) of phenytoin in the course of regulated necrosis. We will first determine at which molecular level of the necrosome the effect of Phenhydan® in cell death inhibition is manifested. In this context, we will establish whether the drug influences NF-kappa B activation and/or the initial education or molecular composition of Complexes I and/or II, which are required for necrotic processes. In view of the broad range of clinical disorders we want to proof whether the inhibitory effect of Phenhydan® in the course of TNF-mediated necroptosis is not only detectable after TNF-stimulation but also by other ligands, and it may even occur in the course of death receptor-mediated apoptosis. Such a superordinate mode of action of an individual drug would be unique. Finally, using preclinical animal models, we will analyze in vivo the therapeutic relevance of Phenhydan® in the course of pathophysiological necrosis.Our overarching aim is the use of Phenhydan®, with its known safety profile, as a first-in-class inhibitor of pathophysiological necroptosis in patients. The originality and innovation of this proposal arise from the potential for immediate transfer of basic research results into the clinic (from bench-to-bedside), which would exemplify the classical criteria of "Translational Medicine".

• DFG Programme: Research Grants