Discovery of isonucleotidic CDNs as potent STING agonists with immunomodulatory potential

Dejmek, Milan; Šála, Michal; Brázdová, Andrea; Vaneková, Lenka; Smola, Miroslav; Klíma, Martin; Břehová, Petra; Budêšínský, Miloś; Dračínský, Martin; Procházková, Eliška; Zavřel, Martin; Šimák, Ondřej; Páv, Ondřej; Bouřa, Evžen; Birkuš, Gabriel; Nencka, Radim

doi:10.1016/j.str.2022.05.012

Cited by 12 publications

(12 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, we observed comparable activities in cell-based reporter assays. When comparing the activities of derivatives 5k–m with those of the clinical candidate ADU-S100, , similar or better activities were observed in digitonin assay. Moreover, in the standard 293T cell-based assay, compounds 5k–m showed lower EC 50 values than ADU-S100.…”

Section: Resultsmentioning

confidence: 99%

“…EC 50 values are the mean of three independent experiments ( n = 3) measured in triplicate with SD < 50% of EC 50 values. c Results of standard assay in 293T reporter cells expressing wt hSTING were obtained as described in the Methods section. EC 50 values are the mean of two independent experiments ( n = 2) measured in triplicate with SD < 50% of EC 50 values. d Data from one experiment only ( n = 1). e Data from Dejmek et al …”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

et al. 2022

Self Cite

View full text Add to dashboard Cite

Cyclic dinucleotides (CDNs) are second messengers that activate stimulator of interferon genes (STING). The cGAS-STING pathway plays a promising role in cancer immunotherapy. Here, we describe the synthesis of CDNs containing 7-substituted 7-deazapurine moiety. We used mouse cyclic GMP−AMP synthase and bacterial dinucleotide synthases for the enzymatic synthesis of CDNs. Alternatively, 7-(het)aryl 7-deazapurine CDNs were prepared by Suzuki−Miyaura cross-couplings. New CDNs were tested in biochemical and cell-based assays for their affinity to human STING. Eight CDNs showed better activity than 2′3′-cGAMP, the natural ligand of STING. The effect on cytokine and chemokine induction was also evaluated. The best activities were observed for CDNs bearing large aromatic substituents that point above the CDN molecule. We solved four X-ray structures of complexes of new CDNs with human STING. We observed π−π stacking interactions between the aromatic substituents and Tyr240 that are involved in the stabilization of CDN-STING complexes.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, Dejmek and colleagues designed a novel class of vinylphosphonate-containing CDNs based on affinity screening tests. [128] The vinyl-modified derivatives exhibit significantly enhanced potency, with their acyloxymethyl phosphonate prodrug (CDNs prodrug 11C, Standard HEK 293T WT STING cell-based reporter assay without transfection reagent EC 50 (STING-WT-30 min) = 0.01 μM, EC 50 (STING-WT-7 h) = 0.012 μM) demonstrating a 1000-fold increase in potency compared to the endogenous ligand…”

Section: Cdns and Its Analogsmentioning

confidence: 99%

“…Subsequently, it advanced to a phase II clinical trial (NCT03937141) in 2019 to evaluate the efficacy of combining pembrolizumab with conventional treatments for head and neck squamous cell carcinoma. Unfortunately, the Phase II clinical trial of ADU‐S100 was terminated in 2021 [120b] . In addition to ADU‐S100 , MK‐1454 (IFN reporter THP‐1 cell‐based assay EC 50 =0.69 μM) represents another promising analog of CDNs.…”

Section: Sting Agonists For Cancer Therapymentioning

confidence: 99%

Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

Xuan,

2023

ChemMedChem

View full text Add to dashboard Cite

Stimulator of interferon genes (STING) is a crucial adaptor protein in the innate immune response. STING activation triggers cytokine secretion, including type Ⅰ interferon and initiates T cell‐mediated adaptive immunity. The activated immune system converts "cold tumors" into "hot tumors" that are highly responsive to T cells by recruiting them to the tumor microenvironment, ultimately leading to potent and long‐lasting anti‐tumor effects. Unlike most immune checkpoint inhibitors, STING agonists represent a groundbreaking class of innate immune agonists that hold great potential for effectively targeting various cancer populations and are poised to become a blockbuster in tumor immunotherapy. This review will focus on the correlation between the STING signaling pathway and tumor immunity, as well as explore the impact of STING activation on other biological processes. Ultimately, we will summarize the development and optimization of STING agonists from a medicinal chemistry perspective, evaluate their potential in cancer therapy, and identify possible challenges for future advancement.

show abstract

“…Compound 22 ( 31 ): Dejmek and co-workers 75 described the discovery of a set of isonucleotidic CDN as a novel class of CDN STING agonists, of which compound 22 showed improved cellular uptake, and consequently enhanced activity up to four orders of magnitude.…”

Section: Small Molecule Immunomodulators Targeting the Innate Immune ...mentioning

confidence: 99%

Small molecule-based immunomodulators for cancer therapy

Yang

Cheng

et al. 2022

Acta Pharmaceutica Sinica B

View full text Add to dashboard Cite

Discovery of isonucleotidic CDNs as potent STING agonists with immunomodulatory potential

Cited by 12 publications

References 46 publications

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

Small molecule-based immunomodulators for cancer therapy

Contact Info

Product

Resources

About