DMXAA

Vadimezan, ASA404, murine STING ligand

DMXAA (also known as Vadimezan or ASA404) was initially identified as a potent tumor vascular disrupting agent in mice.
The antitumor activity of DMXAA has been linked to its ability to induce a variety of cytokines and chemokines, including TNF-α, IP-10, IL-6 and RANTES [1].

DMXAA is also a potent inducer of IFN-β [1,2]. Despite significant preclinical promise, DMXAA failed human clinical trials. Recent studies have demonstrated that DMXAA targets the STING pathway [3], and this in a mouse-specific manner; DMXAA has no effect on human STING [4,5]. A single point mutation (S162A) located within the cyclic-dinucleotide-binding site of human STING has been identified that renders it sensitive to DMXAA [6].

References:

1. Jassar AS. et al., 2005. Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. Cancer Res. 65(24):11752-61.
2. Roberts ZJ. et al., 2007. The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis. J Exp Med. 204(7):1559-69.
3. Prantner D. et al., 2012. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential. J Biol Chem. 287(47):39776-88.
4. Conlon J. et al., 2013. Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. J Immunol. 190(10):5216-25.
5. Kim S. et al., 2013. Anticancer Flavonoids Are Mouse-Selective STING Agonists. ACS Chem Biol. 8(7): 1396-1401.
6. Che X. et al., 2017. Single Mutations Reshape the Structural Correlation Network of the DMXAA-Human STING Complex. J Phys Chem B. 2017 Mar 9;121(9):2073-2082.

Figures

THP1-Dual™ KI-mSTING cells were stimulated with human IFN-β (1 x 104 U/ml), DMXAA (100 µg/ml), 2’3’-cGAMP (30 µg/ml), 3’3’-cGAMP (30 µg/ml), 2’3’-cGAM(PS)₂ (Rp/SP) (30 μg/ml), 3’3’-cGAMP fluorinated (30 µg/ml), 2’3’-c-di-AMP (30 µg/ml), 3’3’-c-di-AMP (30 µg/ml), 2’3’-c-di-AM(PS)₂ (Rp/SP) (30 µg/ml), 2’3’-c-di-GMP (30 µg/ml) and 3’3’-c-di-GMP (30 µg/ml). After 24 hours, NF-κB activation was determined using QUANTI-Blue™ Solution,  a SEAP detection reagent, and by reading the optical density (OD) at 655 nm. 

THP1-Dual™ KI-mSTING cells were stimulated with human IFN-β (1 x 104 U/ml), DMXAA (100 µg/ml), 2’3’-cGAMP (30 µg/ml), 3’3’-cGAMP (30 µg/ml), 2’3’-cGAM(PS)2 (Rp/SP) (30 μg/ml), 3’3’-cGAMP fluorinated (30 µg/ml), 2’3’-c-di-AMP (30 µg/ml), 3’3’-c-di-AMP (30 µg/ml), 2’3’-c-di-AM(PS)2 (Rp/SP) (30 µg/ml), 2’3’-c-di-GMP (30 µg/ml) and 3’3’-c-di-GMP (30 µg/ml). A) After 24 hours, IRF activation was determined by measuring the relative light units (RLUs) in a luminometer using QUANTI-Luc™, a Lucia luciferase detection reagent. The IRF induction of each ligand is expressed relative to that of hIFN-β at 1x10⁴ U/ml (taken as 100%).

Specifications

Description: Mouse STING ligand

Synonym: 5,6-dimethylxanthenone-4-acetic acid

CAS Number: 117570-53-3

Formula: C₁₇H₁₄O₄

Molecular weight: 282.29

Purity: ≥ 97% by UHPLC

Solubility: 10 mg/ml in DMSO

Quality control:

• Biological activity has been assessed by measuring induction of the interferon pathway in cellular assays.
• The absence of endotoxins and other bacterial contaminants has been verified using HEK-Blue™ TLR4 and HEK-Blue™ TLR2 cells.

Contents

• 5 mg of DMXAA

DMXAA is shipped at room temperature

Stored at -20°C.

Product is sterile filtered prior to lyophilization.

Details

DMXAA chemical structure