TEAD inhibitor induced switch in energy metabolism drives human podocyte injury in vitro.

Early detection and understanding of the potential adverse effects of a drug candidate is of utmost importance to reduce the attrition rate during drug development while delivering safe medications to patients. The kidney is one of the most frequently challenged organs involved in drug-induced toxicity, including general glomerulopathy and podocyte- specific cytotoxicity with ensuing overt proteinuria. Whilst TEAD inhibitors address the need for treatment of mesotheliomas and other tumours unaffected by approved drugs, animal testing and clinical trials provide evidence of renal toxicity induced by this novel class of drugs. Here we present an in vitro test system consisting of immortalized human podocytes PODO/TERT256 to characterize the potential adverse effects of TEAD inhibitors. We demonstrate that TEAD inhibitors K-975, IK-930 and VT-107 affect the podocyte monolayer in a wide dose range (33.3-100 µM), disrupt the cellular vesicle system, and subsequently induce cell death, especially after exposure to pan-TEAD inhibitors (VT-107 and K-975). Of note, low micromolar concentrations of TEAD inhibitors lowered mitochondrial oxidative phosphorylation directly after exposure which was confirmed by reduced basal ATP levels after 3 d of exposure. In summary, the in vitro human podocyte model presented can characterize glomerular filtration functionality decline subsequent to TEAD inhibitor exposure and thus represents a promising model for early detection and prediction of potential drug related glomerulopathy in humans.