Nrf2 As A Drug Target
In patients with relapsing-remitting multiple sclerosis, dimethyl fumarate (BG-12, Biogen) significantly reduced relapse and disability progression in a phase 3 trial. Dimethyl furmarate targets the Nrf2 pathway, upregulates Nrf2, and repairs oxidative damage. Similarly, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid trifluoroethyl amide (CDDO-TFEA) showed the potential benefit in both chronic and relapsing-remitting mouse model of multiple sclerosis. In this study pareek et al. demonstrates the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. CDDO-TFEA completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Other drugs that target NFE2L2 are being evaluated as treatment for oxidative-stress related diseases, in animal models or clinical trials.
Bardoxolone methyl is undergoing testing in human clinical trials.
The dithiolethiones are a class of organosulfur compounds, of which oltipraz is the best studied. Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue. However, clinical trials of oltipraz have not demonstrated efficacy and have shown significantside effects, including neurotoxicity and gastrointestinal toxicity. Oltipraz also generates superoxide radical, which can be toxic.
A series of synthetic oleane triterpenoid compounds that are Nrf2 activators and referred to as antioxidant inflammation modulators (AIMs), are in clinical development at Reata Pharmaceuticals. The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), has completed Phase 2 clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus. Data indicate that bardoxolone methyl improves markers of kidney function, including producing a significant increase in estimated glomerular filtration rate that correlates with changes in blood urea nitrogen, serum phosphorus, uric acid, and magnesium. Improvements were sustained over 6 months of therapy and remained significant compared to placebo.) A Phase 3 outcomes study (BEACON) is scheduled to begin in mid-2011.) Reata also indicates that it has other Nrf2 inducers in the same class that are in preclinical development for the treatment of CNS and respiratory diseases.)
Read more about this topic: NFE2L2
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