Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F23%3A00574383" target="_blank" >RIV/61388963:_____/23:00574383 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/00216208:11310/23:10468385 RIV/60461373:22330/23:43926962
Výsledek na webu
<a href="https://doi.org/10.1016/j.ejmech.2023.115685" target="_blank" >https://doi.org/10.1016/j.ejmech.2023.115685</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2023.115685" target="_blank" >10.1016/j.ejmech.2023.115685</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy
Popis výsledku v původním jazyce
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.
Název v anglickém jazyce
Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy
Popis výsledku anglicky
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.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
30107 - Medicinal chemistry
Návaznosti výsledku
Projekt
Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Ostatní
Rok uplatnění
2023
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
European Journal of Medicinal Chemistry
ISSN
0223-5234
e-ISSN
1768-3254
Svazek periodika
259
Číslo periodika v rámci svazku
November
Stát vydavatele periodika
NL - Nizozemsko
Počet stran výsledku
12
Strana od-do
115685
Kód UT WoS článku
001059072400001
EID výsledku v databázi Scopus
2-s2.0-85166974992