Omaveloxolone (RTA-408)

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Background

Omaveloxolone (RTA-408) is a novel synthetic triterpenoid that binds to Kelch-like ECH-associated protein 1 (Keap1) and attenuate nuclear factor erythroid 2-related factor 2 (Nrf2) degradation [1].
Keap1 is involved in proteasomal degradation of Nrf2, thereby maintaining low basal levels of Nrf2. Binding to Keap1 and blocking its ability to promote Nrf2 degradation increase newly synthesized Nrf2 accumulated in the nucleus where Nrf2 increases the expression of antioxidant genes and decreases the expression of pro-inflammatory genes [1].
In interferon-γ-stimulated RAW 264.7 macrophage cells, low concentrations (≤ 25 nM) of RTA-408 activated Nrf2 and lowered nitric oxide and pro-inflammatory cytokine levels. At higher concentrations, RTA-408 inhibited tumor cell growth, with GI50 of 260 ± 74 nM. Meanwhile, RTA-408 increased caspase activity in tumor cell lines, but not in normal primary human cells.
In mice with radiation-induced dermatitis, topical application of RTA-408 (0.01%, 0.1% and 1.0%, q.d.) resulted in dose-dependent improvements in the appearance of skin, with 1.0% RTA-408 markedly reducing epidermal and collagen thickening, preventing dermal necrosis, and completely alleviating skin ulcers [2].

[1]. Probst B L, Trevino I, McCauley L, et al. RTA 408, a novel synthetic triterpenoid with broad anticancer and anti-inflammatory activity. PLoS One, 2015, 10(4): e0122942.
[2]. Reisman S A, Lee C Y, Meyer C J, et al. Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis. Radiation Research, 2014, 181(5): 512-520.