The Stimulator of Interferon Genes (STING) has emerged as a promising target for medicinal chemistry. Agonists of STING, responsible for sensing cellular double-stranded DNA [1], have significantly advanced research in immuno-oncology and instilled hope among patients as potent agents for combined therapies, enhancing the immune system's anti-tumor capabilities.
Our cheminformatics team has prepared a collection of more than 2,600 drug-like screening compounds of predicted STING agonists or antagonists:
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Background
Recent studies have demonstrated that the STING pathway plays a crucial role in the innate immune response to cancer by triggering the production of type-I interferons (IFNs) and promoting robust antitumor activity [2–8]. Small-molecule compounds that stimulate STING-dependent cellular processes have shown promise in enhancing the immune system's ability to target cancer cells and inhibit viral replication [9].
Cyclic dinucleotides (CDNs) are particularly potent activators of the STING pathway. These molecules, which serve as second messengers in prokaryotes [10], are also present in the immune systems of eukaryotes [11]. CDNs are produced through the cGAS pathway or introduced directly into the cytosol in response to pathogenic invasion [12].
The potential of STING agonism in cancer therapy is particularly relevant in the context of novel immunotherapies. While treatments like checkpoint inhibitors have become essential in combating various cancers, they are less effective against “cold” or “non-T cell-inflamed” tumors, which lack sufficient T cell infiltration or exhibit immune suppression. To address this challenge, activating the innate immune system through established signaling pathways, such as toll-like receptor (TLR) 7/8, nucleotide-binding oligomerization domain (NOD), and cGAS-STING, is an encouraging strategy. Preclinical studies have shown that using STING agonists, such as cGAMP or other CDN derivatives, holds significant potential as an anti-cancer therapeutic approach.
STING Targeted Library
The STING Targeted Library was designed by means of docking-based virtual screening. The X-ray data of the dimeric form of STING bound to cyclic di-GMP (PDB ID: 4F9G) were employed as a reference. In this process, confirmation the formation of at least one hydrogen bond with Thr263 was established as an obligatory docking constraint, as illustrated in Figure 1. The docking score value is available for each compound in the compound structure file.
Key features:
- Method: SP (standard precision) ligand-receptor docking
- X-Ray data used: 4F9G
- Constraints: H-bond (Thr263)
- Filters used: no
- Number of compounds selected: 1,602
Figure 1. Compound F6656-4275 in the STING dimer binding site. The model was obtained by molecular docking.
STING Focused Library
This Screening Set was designed using a similarity search based on a reference set of bioactive compounds with reported activity against STING (IC50, Ki, etc., ≤ 10 µM, Inhibition > 25 %). It was prepared based on data from the PubChem and ChEMBL databases. The Life Chemicals HTS Compound Collection was then analyzed for close structural analogs by several 2D similarity methods (MDL public keys; long-range functional class fingerprint – FCFP) and the 75 % Tanimoto and Tversky similarity cut-off. Reactive, toxic, and PAINS molecules were excluded, resulting in around 1,000 drug-like screening compounds.
Representative screening compounds from the STING-targeting Screening Library
References
- Tripathi S, Najem H, Mahajan AS, Zhang P, Low JT, Stegh AH, Curran MA, Ashley DM, James CD, Heimberger AB. cGAS-STING pathway targeted therapies and their applications in the treatment of high-grade glioma. F1000Res. 2022 Sep 7;11:1010. doi: 10.12688/f1000research.125163..
- 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).
- 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).
- Luo K, Li N, Ye W, Gao H, Luo X, Cheng B. Activation of Stimulation of Interferon Genes (STING) Signal and Cancer Immunotherapy. Molecules. 2022 Jul 20;27(14):4638. doi: 10.3390/molecules27144638
- 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).
- 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).
- Paulis, A.; Tramontano, E. Unlocking STING as a Therapeutic Antiviral Strategy. Int. J. Mol. Sci.2023, 24, 7448. https://doi.org/10.3390/ijms24087448
- 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).
- 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.
- Gomelsky M. cAMP, c-di-GMP, c-di-AMP and now cGMP: bacteria use them all! Mol. Microbiol. 79(3), 562–565 (2011).
- Krasteva PV, Sondermann H. Versatile modes of cellular regulation via cyclic dinucleotides. Nat. Chem. Biol. 13(4), 350–359 (2017).
- 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).