Rational design and synthesis of edaravone- remyelinating analogues and probes: a preliminary SAR

The main focus of regenerative therapies for MS is to induce the differentiation of oligodendrocyte progenitor cells (OPC) present within areas of demyelination into remyelinating oligodendrocytes. We have recently performed a multiple phenotypic screen with the aim of repositioning drugs according to their myelin repair potential (Eleuteri et al., 2017). This work has led to the identification and validation of edaravone as a hit compound. This is a small bioactive molecule that easily crosses the blood brain barrier, and was approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis (ALS) in Japan first, and more recently in the US for ALS. In this multi-disciplinary project we plan to identify the protein(s) through which edaravone elicits the remyelinating phenotype, and to confirm both the drug-target engagement and the remyelinating activity of the identified target(s). These goals will be achieved by combining a mass spectrometry-based photoaffinity labeling approach on edaravone-based probes, cellular thermal shift assay (CETSA) and test of known modulators of the identified targets in purified mouse OPC