R970, A Selective Activator of Nrf2, is Efficacious in a Murine Model of Multiple Sclerosis

Abstract

Abstract The transcription factor Nrf2 (nuclear factor erythroid-derived-2-like 2) is a key mediator of the anti-oxidant response. Nrf2 can be activated by alkylating its chaperone, Keap-1, resulting in a retardation of Nrf2 degradation, and increased Nrf2 in the cytoplasm. Upon translocation to the nucleus, Nrf2 binds an Antioxidant Response Element (ARE), which leads to the transcription of antioxidant gene products, many of which may be cytoprotective. Activation of the Nrf2 pathway may be useful against a wide-range of disorders, such as multiple sclerosis, psoriasis, and Huntington’s Disease, among others. For example, monomethylfumarate (MMF), the active component of the multiple sclerosis drug, dimethylfumarate (DMF), has been shown to activate the Nrf2-pathway at therapeutic concentrations. However, MMF also serves as an agonist of the niacin receptor, which is likely responsible for the flushing side-effect seen in patients taking DMF. We have discovered a novel class of molecules that are potent activators of Nrf2 and are inactive at the niacin receptor, yet are efficacious in vivo in a model of multiple sclerosis. Lead candidate R970 is an orally-bioavailable small molecule activator of Nrf2 (EC50 = 1 uM; MMF EC50 = 127 uM), which is inactive at the niacin receptor (0% activity at 500 uM; MMF EC50 ca. 1 uM). Additionally, R970 is selective against a range of kinase, G-protein-coupled receptor, ion-channel, and transporter targets. When dosed orally in a murine model of multiple sclerosis, R970 delayed the onset and also suppressed clinical disease. Further exploration with R970 and other selective activators of Nrf2 is ongoing and may yield a next-generation Nrf2-therapeutic, with an improved side-effect profile.