Targeting STING with covalent small-molecule inhibitors

• Published in: Nature (London) Vol. 559; no. 7713; pp. 269 - 273
• Main Authors: Haag, Simone M., Gulen, Muhammet F., Reymond, Luc, Gibelin, Antoine, Abrami, Laurence, Decout, Alexiane, Heymann, Michael, van der Goot, F. Gisou, Turcatti, Gerardo, Behrendt, Rayk, Ablasser, Andrea
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2018; Nature Publishing Group
• Subjects: 49; 49/98; 631/250/262; 631/250/516; Activation; Amino acids; Animals; Antagonists; Binding Sites; Biological response modifiers; Cell Line; Chemical bonds; Cysteine; Cysteine - metabolism; Cystine; Deoxyribonucleic acid; Disease; DNA; DNA sequencing; Drug development; Gene expression; Golgi apparatus; Golgi Apparatus - drug effects; Golgi Apparatus - metabolism; Health aspects; Hereditary Autoinflammatory Diseases - drug therapy; Hereditary Autoinflammatory Diseases - metabolism; Humanities and Social Sciences; Humans; Immune response; Immunosuppressive agents; Inflammation; Inhibitors; Interferon; Intracellular signalling; Kinases; Letter; Lipoylation - drug effects; Lupus; Mass spectrometry; Membrane Proteins - antagonists & inhibitors; Methods; Mice; Mice, Inbred C57BL; Molecular modelling; multidisciplinary; Observations; Palmitoylation; Pharmacology; Protein Binding - drug effects; Proteins; Science; Science (multidisciplinary); Scientific imaging; Signal transduction; Signal Transduction - drug effects; Small Molecule Libraries - analysis; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism; Small Molecule Libraries - pharmacology; Stimulators; Stings (Injuries); Target recognition; United States > US
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0287-8

Aberrant activation of innate immune pathways is associated with a variety of diseases. Progress in understanding the molecular mechanisms of innate immune pathways has led to the promise of targeted therapeutic approaches, but the development of drugs that act specifically on molecules of interest remains challenging. Here we report the discovery and characterization of highly potent and selective small-molecule antagonists of the stimulator of interferon genes (STING) protein, which is a central signalling component of the intracellular DNA sensing pathway
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. Mechanistically, the identified compounds covalently target the predicted transmembrane cysteine residue 91 and thereby block the activation-induced palmitoylation of STING. Using these inhibitors, we show that the palmitoylation of STING is essential for its assembly into multimeric complexes at the Golgi apparatus and, in turn, for the recruitment of downstream signalling factors. The identified compounds and their derivatives reduce STING-mediated inflammatory cytokine production in both human and mouse cells. Furthermore, we show that these small-molecule antagonists attenuate pathological features of autoinflammatory disease in mice. In summary, our work uncovers a mechanism by which STING can be inhibited pharmacologically and demonstrates the potential of therapies that target STING for the treatment of autoinflammatory disease.
The discovery and characterization of small-molecule antagonists that inhibit the stimulator of interferon genes (STING) protein may help to develop therapies for the treatment of autoinflammatory disease.