Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons

The fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) demethylase, is important regulator of central nervous system development, neuronal signaling disease. We present here the target-tailored development biological characterization small-molecule inhibitors FTO. active compounds were identified using high-throughput molecular docking dynamics screening ZINC compound library. In FTO binding activity-inhibition assays two best demonstrated Kd = 185 nM; IC50 1.46 µM (compound 2) 337 28.9 3). Importantly, treatment mouse midbrain dopaminergic neurons with promoted cellular survival rescued them from growth factor deprivation induced apoptosis already at nanomolar concentrations. Moreover, both good blood-brain-barrier penetration in model system, 31.7% 30.8%, respectively. increased potency as compared to our recently developed ALKBH5 m6A demethylase protecting dopamine neurons. Inhibition demethylation by drugs, presented here, has therapeutic potential provides tools for identification disease-modifying RNAs neurogenesis neuroregeneration. Further refinement lead this study can also unprecedented breakthroughs neurodegenerative diseases.