DMXAA - Non-nucleotide-based Mouse-specific STING Agonist

DMXAA (Vadimezan, ASA404) small molecule - Mouse STING ligand

DMXAA 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.