Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy

0574383 - ÚOCHB 2024 RIV NL eng J - Journal Article
Dejmek, Milan - Brázdová, Andrea - Otava, Tomáš - Pimková Polidarová, Markéta - Klíma, Martin - Smola, Miroslav - Vavřina, Zdeněk - Buděšínský, Miloš - Dračínský, Martin - Liboska, Radek - Bouřa, Evžen - Birkuš, Gabriel - Nencka, Radim
Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy.
European Journal of Medicinal Chemistry. Roč. 259, November (2023), č. článku 115685. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA MŠMT(CZ) LX22NPO5103; GA MZd(CZ) NU20-05-00472
Research Infrastructure: CCP II - 90126
Institutional support: RVO:61388963
Keywords : cyclic dinucleotides * STING * cancer * intratumoral administration * immunotherapy
OECD category: Medicinal chemistry
Impact factor: 6.7, year: 2022
Method of publishing: Open access
https://doi.org/10.1016/j.ejmech.2023.115685

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.
Permanent Link: https://hdl.handle.net/11104/0344716


Research data: PDB