Targeting STING with covalent small-molecule inhibitors

By S. M. Haag, M. F. Gulen, L. Reymond, Antoine Gibelin, L. Abrami, A. Decout, Michael Heymann, F. G. van der Goot, G. Turcatti, R. Behrendt and 1 more. Nature, 2018

1,020 citations recorded by the source corpus.

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 pathway1,2. 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.

Subfields: Immunology, Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3b597693bde83fd7f8b581dcf716e14452ef802d

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Jesús Gil
2. S. Tait
3. Joel S. Riley

In Infectious Diseases

1. S. Tait
2. Joel S. Riley

In Molecular Biology

1. Jesús Gil
2. S. Tait
3. Joel S. Riley
4. S. Masters
5. Jodie Birch

Citations in the corpus

• Mitochondrial DNA in inflammation and immunity (2020, positive): “Small molecules targeting both cGAS [115,116] and STING [117] have been developed, with STING antagonists emerging as the most promising.”
• TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS (2020, background): “Given that a range of cGAS and STING inhibitors have been developed recently (Haag et al., 2018; Vincent et al., 2017), including those which we have shown here to prevent TDP-43-induced inflammation, it should be possible to determine whether targeting this pathway can improve the symptoms of neuro”
• Senescence and the SASP: many therapeutic avenues (2020, background): “The cGAS/STING pathway is considered a key regulator of SASP induction (Dou et al. 2017; Glück et al. 2017; Yang et al. 2017).”