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STING Targeted Library

STING (Stimulator of Interferon Genes) has become a promising drug target for medicinal chemists. Agonists of the cellular double-stranded DNA sensor STING [1] have boosted the immuno-oncology field of research and raised hope for patients as powerful agents for combined therapies, by further harnessing the antitumor potential of the immune system. Evidence from recent studies has identified the host STING pathway as a critical mechanism of innate immune-sensing of cancer, driving the production of type-I IFNs and promoting aggressive antitumor responses [2–9]. Small molecules capable of triggering STING-dependent cellular processes are effective at facilitating immune response to cancer cells and blocking virus replication.

Among natural ligands, cyclic dinucleotides (CDNs) are especially potent activators of STING that are ubiquitous second messengers in prokaryotes [10] and within the immune system of eukaryotic species [11]. These CDNs are produced either through the cGAS pathway or are directly found in the cytosol due to the presence of pathogens [12].

The STING Targeted Library has been created by docking-based virtual screening using X-ray data for dimer form of STING in complex with cyclic di-GMP (PDB ID: 4F9G). The formation of at least 1 H-bond with Thr263 has been used as an obligatory docking constraint during screening (Fig. 1).

The selected 1,600 drug-like screening compounds of potential STING agonists and antagonists that comprise the Library are Ro5-compliant and do not contain reactive and toxic groups. The docking score value is available for each compound in the compound structure file provided on requests.

Molecular docking of the compound F6548-1965 in the STING dimer binding site

Figure 1. Compound F6548-1965 in the STING dimer binding site. The model obtained by molecular docking.

References

  1. Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455(7213), 674–678 (2008).
  2. Corrales L, Gajewski TF. Molecular pathways: targeting the stimulator of interferon genes (STING) in the immunotherapy of cancer. Clin. Cancer Res. 21(21), 4774–4779 (2015).
  3. Curran E, Chen X, Corrales L et al. STING pathway activation stimulates potent immunity against acute myeloid leukemia. Cell Rep. 15(11), 2357–2366 (2016).
  4. Clinical Trials Database: NCT03172936. https://clinicaltrials.gov/ct2/show/NCT03172936
  5. Demaria O, De Gassart A, Coso S et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc. Natl Acad. Sci. USA 112(50), 15408–15413 (2015).
  6. Fu J, Kanne DB, Leong M et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl. Med. 7(283), 283ra52 (2015).
  7. Wang Z, Celis E. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice. Cancer Immunol. Immunother. 64(8), 1057–1066 (2015).
  8. Corrales L, Glickman LH, McWhirter SM et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11(7), 1018–1030 (2015).
  9. Cui, X.; Zhang, R.; Cen, S.; Zhou, J. STING Modulators: Predictive Significance in Drug Discovery. European Journal of Medicinal Chemistry 2019, 182, 111591. https://doi.org/10.1016/j.ejmech.2019.111591.
  10. Gomelsky M. cAMP, c-di-GMP, c-di-AMP and now cGMP: bacteria use them all! Mol. Microbiol. 79(3), 562–565 (2011).
  11. Krasteva PV, Sondermann H. Versatile modes of cellular regulation via cyclic dinucleotides. Nat. Chem. Biol. 13(4), 350–359 (2017).
  12. Zhang X, Shi H, Wu J et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51(2), 226–235 (2013).

 

 

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