A novel small molecule remyelination therapy for multiple sclerosis.

We conducted a phenotypic screen of 20,000 central nervous system (CNS)-biased small molecules for their ability to stimulate differentiation of mouse oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. We identified a lead hit (CN045) with an EC50 of 40 nM in the OPC differentiation assay and a chemical scaffold conducive to modifications. In OPC differentiation assays, CN045 demonstrated higher potency than a known OPC differentiation compound Triiodothyronine (T3). CN045 promoted myelin-like ensheathment of engineered nanofibers by mouse and human OPCs and significantly increased remyelination in white and gray matter regions of mouse brain following cuprizone/rapamycin-induced demyelination. In terms of pharmacokinetics, CN045 is CNS-penetrable with low cytotoxicity. CN045 has a short half-life in vivo, but its chemical scaffold is conducive to structural modifications that can improve its metabolic properties. Collectively, these results demonstrate that CN045 is an attractive lead candidate for enhancing OPC differentiation and remyelination in multiple sclerosis patients.