Amyotrophic Lateral Sclerosis is a severe neurodegenerative disease characterized by the degeneration of the upper and lower motor neurons (MN), ultimately leading to patient death by respiratory failure. Despite being the most common adult-onset motor neuron disease, the drugs available till now are symptomatic and only extend patients life expectancy a few months without changing the onset of the disease. Recent studies revealed that NF-κB transcription factor is the major regulator of neuroinflammation in ALS. Therefore, inhibitors of NF-κB signalling pathway can be considered key tools for the development of novel therapies for ALS. Additionally, the use of iron chelators have also shown potential to increase ALS survival through the regulation of iron redox activity and by triggering MN cell survival mechanisms through the mild activation of HIF transcriptional factor. In this project we propose an innovative therapeutic solution for ALS based on the design and syntheses of multitarget small-molecules capable to modulate NF-κB activity through inhibition of IKKβ protein and prevent/minimize the iron induced oxidative damage and/or stabilize HIF. The project encompasses the rational design and synthesis of a library of small molecules that will be submitted to an initial cascade of biophysical and chemical assays to evaluate their binding affinity and iron chelation properties. Subsequently ALS cellular models will be used in order to validate target engagement inside cells, as well as, to identify the small-molecules that could protect MN from oxidative-stress and inflation driven apoptosis. At the end of the project it is expected to propose a novel lead compound that will be optimized and its performance evaluated in ALS animal models. This project combines the expertise available in academia and industry to validate a new therapeutic approach for ALS and, provides an exceptional training opportunity to prepare a young researcher for his future career.