The abnormal activation of innate immune pathways partispate in the progress of various diseases. Unfortunately, the development of drugs specifically targeted molecules with interest and potential still remains challenging. A recent study from Simone M. Haag, et al. reported the discovery and characterization of C-176. The novel molecular is a highly selective, small-molecule antagonist of STING protein. By the way, STING is short for stimulator of interferon genes, also known as transmembrane protein 173 and plays an important role in innate immunity by inducing type I interferon production.
In the study, the authors identified a nitrofuran derivative-C-176 by performing a cell based chemical screen. The compound strongly reduces STING-mediated, rather than RIG-I- or TBK1-mediated, IFNβ reporter activity. Then, a series of experiments verified that C-176 directly targets mouse STING (mmSTING), and this didn’t happen in human STING (hsSTING). Notably, C-176 treated Trex1−/− mice shows a significant reduction in serum levels of type I IFNs. Besides, C-176 also results in a strong suppression of inflammatory parameters in the heart of Trex1−/− mice. Morever, wild-type mice on a two-week treatment with C-176 show no evident signs of overt toxicity. Subsequently, the researchers conducted a three-month trial with C-176 in Trex1−/− mice, which demonstrated marked amelioration of various signs of systemic inflammation.
Not only that, the study also identified the covalent modification of Cys91 of mmSTING covalently C-176. Interestingly, another compound C-178, is also a covalent small-molecule inhibitor of STING. The inhibitor could selectively and potently suppress the STING responses elicited by distinct bona fide activators. However, C-178 didn’t affect the STING response in human, either.
To sum up, the innovative study revealed the inhibitory mechanism of STING on pharmacology, and showed the potential of STING inhibitors in the treatment of autoinflammatory diseases.