7Q85

Crystal structure of human STING in complex with MD1193

Summary for 7Q85

• Entry DOI: 10.2210/pdb7q85/pdb
• Descriptor: Stimulator of interferon genes protein, 9-[(1R,6R,8R,13E,15R,17R,18R)-17-(6-aminopurin-9-yl)-9,18-bis(fluoranyl)-3,12-bis(oxidanyl)-3,12-bis(oxidanylidene)-2,4,7,11,16-pentaoxa-3$l^{5},12$l^{5}-diphosphatricyclo[13.3.0.0^{6,10}]octadec-13-en-8-yl]purin-6-amine (3 entities in total)
• Functional Keywords: sting, antiviral, activator, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 23847.47

Authors

Smola, M.,Klima, M.,Boura, E. (deposition date: 2021-11-10, release date: 2022-10-19, Last modification date: 2024-02-07)

Primary citation

Dejmek, M.,Brazdova, A.,Otava, T.,Polidarova, M.P.,Klima, M.,Smola, M.,Vavrina, Z.,Budesinsky, M.,Dracinsky, M.,Liboska, R.,Boura, E.,Birkus, G.,Nencka, R.
Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy.
Eur.J.Med.Chem., 259:115685-115685, 2023

PubMed Abstract: Cyclic dinucleotides (CDNs) trigger the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which plays a key role in cytosolic DNA sensing and thus in immunomodulation against infections, cell damage and cancer. However, cancer immunotherapy trials with CDNs have shown immune activation, but not complete tumor regression. Nevertheless, we designed a novel class of CDNs containing vinylphosphonate based on a STING-affinity screening assay. In vitro, acyloxymethyl phosphate/phosphonate prodrugs of these vinylphosphonate CDNs were up to 1000-fold more potent than the clinical candidate ADU-S100. In vivo, the lead prodrug induced tumor-specific T cell priming and facilitated tumor regression in the 4T1 syngeneic mouse model of breast cancer. Moreover, we solved the crystal structure of this ligand bound to the STING protein. Therefore, our findings not only validate the therapeutic potential of vinylphosphonate CDNs but also open up opportunities for drug development in cancer immunotherapy bridging innate and adaptive immunity.

PubMed: 37567057
DOI: 10.1016/j.ejmech.2023.115685

Experimental method

X-RAY DIFFRACTION (2.359 Å)