Omaveloxolone (RTA-408) (Synonyms: Omaveloxolone)

RTA-408 is an antioxidant inflammation modulator (AIM), which activates Nrf2 and suppresses nitric oxide (NO). RTA-408 attenuates osteoclastogenesis by inhibiting STING dependent NF-κb signaling.

To evaluate the anti-inflammatory activity of RTA-408, RAW 264.7 mouse macrophage cells are treated with RTA-408 for two hours and then IFNγ is added to stimulate NO production and release into the media. RTA-408 dose-dependently reduces NO concentrations in the media with an IC50 value of 4.4±1.8 nM. The potency of RTA-408 in this assay is similar to that of Bardoxolone methyl, which has an IC50 value of 1.9±0.8 nM. Nrf2 activation is required for AIM-mediated NO suppression. A decrease in nitric oxide synthase 2 (Nos2) protein levels is observed in bardoxolone methyl-treated RAW 264.7 cells, which is attenuated when Nrf2 mRNA levels are reduced by siRNA. To evaluate the anticancer activity of RTA-408, a panel of eight human cell lines derived from tumors of different origin are treated with RTA-408 and measured cell growth 72 hours later using the sulforhodamine B (SRB) assay. RTA-408 inhibits the growth of all tumor lines with an average GI50 value of 260±74 nM. To determine whether RTA-408 induces apoptosis, the panel of tumor cells are treated with RTA-408 and the caspase substrate, DEVD-AFC, for 24 hours. RTA-408 dose-dependently increases DEVD-AFC cleavage, indicating that RTA-408 treatment triggers caspase activation in cancer cells. Caspase-3 and caspase-9 cleavage is also observed by western blot at the same concentrations of RTA-408 that increases DEVD-AFC cleavage[1].

To determine whether RTA-408 is an effective mitigator of hematopoietic acute radiation syndrome after bone marrow-lethal doses of total-body irradiation (TBI), mice are administered 3 daily injections of 17.5 mg/kg RTA-408 beginning 24 h after TBI. Teatment with RTA-408 results in the 35 day survival of 100% of 7 Gy (LD40/35) TBI mice (P<0.05) and 60% of 7.5 Gy (LD100/13) TBI mice (P<0.0001)[2].

References:
[1]. Probst BL, et al. RTA 408, A Novel Synthetic Triterpenoid with Broad Anticancer and Anti-Inflammatory Activity. PLoS One. 2015 Apr 21;10(4):e0122942.
[2]. Peng Han, et al. RTA-408 Protects Kidney from Ischemia-Reperfusion Injury in Mice via Activating Nrf2 and Downstream GSH Biosynthesis Gene. Oxid Med Cell Longev. 24 December 2017.
[3]. Goldman DC, et al. The triterpenoid RTA 408 is a robust mitigator of hematopoietic acute radiation syndrome in mice. Radiat Res. 2015 Mar;183(3):338-44