RTA-408 (Omaveloxolone)

Catalog No.	APIM050407
Product Name	RTA-408 (Omaveloxolone)

Description

APIM050407: 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.

CAS No.: 1474034-05-3
IUPAC/Chemical Name: N-((4aR,6aR,6bS,12aS,14aR,14bR)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-4a-yl)-2,2-difluoropropanamide
Molecular Formula: C₃₃H₄₄F₂N₂O₃
Molecular Weight: 554.71
Purity: >99% Purity
QC: Achiral and Chiral HPLCs, MS, NMR, and Quantitative Elemental Analysis Report
Solubility: Soluble in DMSO
Storage: Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).
Note: Please contact us for COA, Spectra, and SDS information.

Background Information:

Antioxidant inflammation modulators (AIMs) include synthetic derivatives of oleanolic acid, a triterpenoid found in medicinal plants. As a class, the AIMs exhibit potent anti-inflammatory and anti-carcinogenic activity due to their ability to activate the transcription factor nuclear factor, erythroid 2-like 2 (NFE2L2 or Nrf2) and inhibit the activity of nuclear factor kappa B (NF-κB). Oleanolic acid itself is a weak Nrf2 activator; however, key alterations to the triterpenoid scaffold improved potency by more than 6 orders of magnitude. The adaptor protein Kelch-like ECH-associated protein 1 (Keap1) targets Nrf2 for Cul3-Rbx1-mediated ubiquitination and constitutive proteasomal degradation, thereby maintaining low basal levels of Nrf2. AIMs increase Nrf2 levels by binding to Keap1 and blocking its ability to promote Nrf2 degradation. As a result, newly synthesized Nrf2 accumulates in the nucleus where it increases the expression of antioxidant genes and decreases the expression of pro-inflammatory genes. [1]

The Keap1/Nrf2 pathway is the primary target of AIMs at lower concentrations that reduce oxidative stress and inflammation. However, multiple oncogenic signaling pathways are modulated at higher concentrations of AIMs that inhibit tumor cell growth. For example, AIMs directly inhibit NF-κB signaling by binding to inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB or IKKβ). Other proteins that are dysregulated in cancer are also affected by AIMs, including: JNK; JAK1 and STAT3; Her2 (ERBB2); death receptor 5 (TNFRSF10B); and cFLIP (CFLAR). By modulating the activity of these proteins in the tumor and reducing oxidative stress and inflammation in the tumor microenvironment, AIMs inhibit several pro-tumor processes, including cell proliferation, angiogenesis, inflammation, metastasis, tumor-mediated immune evasion, and suppression of apoptosis. [1]

Bardoxolone methyl (RTA 402, CDDO-Me) is an AIM with potent anticancer activity in vitro and in animal models. Doses of bardoxolone methyl that increased expression of the classic Nrf2 target gene NQO1 and decreased tumor levels of NF-κB and cyclin D1 were well-tolerated by patients with advanced malignancies in a phase 1 trial (ClinicalTrials.gov ID: NCT00529438). In this trial, one patient with mantle cell lymphoma exhibited a complete response and another with anaplastic thyroid carcinoma exhibited a partial response that lasted 18 months. These promising preliminary findings support continued development of AIMs as a novel approach to cancer treatment.

A novel compound in the AIM class, RTA-408 (Omaveloxolone) (CAS No.: 1474034-05-3), is currently under investigation in a phase 1 clinical trial in patients with metastatic non-small cell lung cancer or melanoma (clinicaltrials.gov ID: NCT02029729). The anti-inflammatory activity of RTA 408 was recently demonstrated in a model of radiation-induced dermatitis, but its anticancer activity has not previously been reported. In the present study, we evaluated the effect of RTA 408 on tumor cell growth, apoptosis, and oncogenic signaling pathways. We first evaluated the potency of RTA 408 as an activator of Nrf2 and an inhibitor of inflammation in the RAW 264.7 mouse macrophage cell line.

Omaveloxolone (RTA-408) is a second generation member of the synthetic oleanane triterpenoid compounds and currently in clinical development by Reata Pharmaceuticals. Preclinical studies have demonstrated that omaveloxolone possesses antioxidative and anti-inflammatory activities and the ability to improve mitochondrial bioenergetics. Omaveloxolone is currently under clinical investigation for a variety of indications, including Friedreich’s ataxia, mitochondrial myopathies, immunooncology, and prevention of corneal endothelial cell loss following cataract surgery.

The effects of omaveloxolone and related synthetic triterpenoid compounds have been documented in over 200 peer-reviewed scientific manuscripts. The mechanism of action of omaveloxolone and its related compounds has been demonstrated to be through a combination of activation of the antioxidative transcription factor Nrf2 and inhibition of the pro-inflammatory transcription factor NF-κB.

Nrf2 transcriptionally regulates multiple genes that play both direct and indirect roles in producing antioxidative potential and the production of cellular energy (i.e., adenosine triphosphate or ATP) within the mitochondria. Consequently, unlike exogenously administered antioxidants (e.g., vitamin E or Coenzyme Q10), which provide a specific and finite antioxidative potential, omaveloxolone, through Nrf2, broadly activates intracellular and mitochondrial antioxidative pathways, in addition to pathways that may directly increase mitochondrial biogenesis (such as PGC1α) and bioenergetics.

Target: Nrf2

IC₅₀: 4.4 ± 1.8 nM

In Vitro: To evaluate the anti-inflammatory activity of Omaveloxolone (RTA 408), RAW 264.7 mouse macrophage cells are treated with Omaveloxolone for two hours and then IFNγ is added to stimulate NO production and release into the media. Omaveloxolone dose-dependently reduces NO concentrations in the media with an IC50 value of 4.4±1.8 nM. The potency of Omaveloxolone 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 Omaveloxolone, a panel of eight human cell lines derived from tumors of different origin are treated with Omaveloxolone and measured cell growth 72 hours later using the sulforhodamine B (SRB) assay. Omaveloxolone inhibits the growth of all tumor lines with an average GI50 value of 260±74 nM. To determine whether Omaveloxolone induces apoptosis, the panel of tumor cells are treated with Omaveloxolone and the caspase substrate, DEVD-AFC, for 24 hours. Omaveloxolone dose-dependently increases DEVD-AFC cleavage, indicating that Omaveloxolone treatment triggers caspase activation in cancer cells. Caspase-3 and caspase-9 cleavage is also observed by western blot at the same concentrations of Omaveloxolone that increases DEVD-AFC cleavage.[1]

In Vivo: To determine whether Omaveloxolone (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 Omaveloxolone beginning 24 h after TBI. Teatment with Omaveloxolone 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] What is the solubility of Omaveloxolone (RTA-408) in vitro?
DMSO: > 100 mg/mL

What is the solubility of Omaveloxolone (RTA-408) in vivo?
DMSO and corn oil
Please add 0% DMSO and 90% corn oil in order, solubility ≥ 2.5 mg/mL.

Reference:
[1]. Probst, B. L. et al. “RTA 408, A Novel Synthetic Triterpenoid with Broad Anticancer and Anti-Inflammatory Activity”, PLoS One, 2015, 10, e0122942
[2]. Han, P. et al. “RTA-408 Protects Kidney from Ischemia-Reperfusion Injury in Mice via Activating Nrf2 and Downstream GSH Biosynthesis Gene”, Oxid. Med. Cell. Longev. 2017, 2017, Article ID 7612182
[3]. Sun, X. et al. “The Nrf2 activator RTA-408 attenuates osteoclastogenesis by inhibiting STING dependent NF-κb signaling”, Redox Biol. 2020, 28, 101309.
[4]. Reisman, S. A. et al. “Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers”, BMC Dermatology 2015, 15, https://doi.org/10.1186/s12895-015-0029-7.
[5]. Tsai, T. H. et al. “Mechanisms and therapeutic implications of RTA 408, an activator of Nrf2, in subarachnoid hemorrhage–induced delayed cerebral vasospasm and secondary brain injury”, PLoS One 2020, https://doi.org/10.1371/journal.pone.0240122.
[6]. Reisman, S. A. et al. “Topical Application of the Synthetic Triterpenoid RTA 408 Protects Mice from Radiation-Induced Dermatitis”, Radiation Research 2014, 181, 512-520
[7]. Yang, C.-C. et al. “RTA 408 Inhibits Interleukin-1β-Induced MMP-9 Expression via Suppressing Protein Kinase-Dependent NF-κB and AP-1 Activation in Rat Brain Astrocytes”, Int. J. Mol. Sci. 2019, 20, 2826; https://doi.org/10.3390/ijms20112826

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