The xanthones are a diverse class of natural products that can be extracted from plants, fungi, lichen, and invertebrates. They have a wide range of biological activities, including antitumor and antimicrobial activity.
DMXAA, a synthetic derivative of xanthone, attracted particular interest in the 2000s because it disrupts tumor blood supply in mice. In 2008 it entered Phase III clinical trials for non-small cell lung cancer. It failed to show benefit in humans.
Recently, Shih et al. investigated the failure of DMXAA to translate across species. In mice, DMXAA activates the STING (stimulator-of-interferon-
The binding pockets of human and mouse STING are identical. So what causes the difference in DMXAA effectiveness? Shih et al. used molecular dynamics, a computational method that simulates the movements of molecules. When they simulated the binding of DMXAA to human STING and mouse STING, they found that the lid of mouse STING remains closed, preventing bound DMXAA from leaving. In human STING, the DMXAA leaves. A peptide residue in the STING lid region is responsible for the difference.
This work may aid in the rational design of a STING activator, but the researchers conclude that the design of such a drug would be challenging.
Shih AY, Damm-Ganamet KL, Mirzadegan T. Dynamic Structural Differences between Human and Mouse STING Lead to Differing Sensitivity to DMXAA. 2018. Biophysical Journal. DOI: 114:32-39.