scispace - formally typeset

Cyclic dinucleotides as agonists of stimulator of interferon gene dependent signalling

02 Mar 2021-
Abstract: Disclosed herein are new cyclic dinucleotide compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of modulation of immune response to disease, and induce Stimulator of Interferon Genes (STING) dependent type I interferon production and co-regulated genes in a human or animal subject are also provided for the treatment diseases such as cancer, particularly metastatic solid tumors and lymphomas, inflammation, allergic and autoimmune disease, infectious disease, and for use as anti-viral agents and vaccine adjuvants.

... read more

Topics: Stimulator of interferon genes (68%), Interferon (53%), Autoimmune disease (52%) ... read more

7 results found

Boyu Zhong1, Lijun Sun1, Heping Shi1, Qi Wei1  +3 moreInstitutions (1)
17 Mar 2017-
Abstract: Disclosed are cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy.

... read more

57 Citations

06 Jul 2017-
Abstract: This invention relates to compounds and compositions for the induction of expression of a pattern recognition receptor (e.g., STING) and methods of use thereof.

... read more

Topics: Sting (56%)

21 Citations

23 Oct 2018-
Abstract: Various compositions are disclosed. The compositions of conjugates comprising immune-modulatory agents are also provided. Additionally provided are the methods of preparation and use of the conjugates. This includes methods for treating disorders, such as cancer and fibrosis.

... read more

12 Citations

Journal ArticleDOI: 10.2174/1568026619666191010155903
Yiqian Lian1, Kevin J. Duffy1, Jingsong Yang1Institutions (1)
Abstract: Recent regulatory approval of several immune checkpoint inhibitors has ushered in a new era of cancer immunotherapies with the promise of achieving a durable response. This represents a paradigm shift in cancer treatment from directly targeting tumor cells to harnessing the power of a patient's own immune system to destroy them. The cGAS-STING pathway is the major cytosolic dsDNA sensing pathway that plays a pivotal role in the innate antitumor immune response. With a fundamentally different mode of action (MOA) than immune checkpoint modulators, STING activation can potentially enhance tumor immunogenicity and improve patient responses as a single agent or by synergizing with existing anti-cancer drugs. Therefore, there has been intense interest from the pharmaceutical industry and academic institutions in the search for potent STING agonists as immunotherapies in oncology. In this article, we review briefly the cGAS-STING pathway and STING agonists that are in the clinical and preclinical studies, summarize recently disclosed patent applications and published journal articles in the field and cover both cyclic dinucleotide (CDN) analogs and non-nucleic acid derived STING agonists.

... read more

Topics: Immune checkpoint (56%), Sting (53%)

8 Citations

19 Mar 2020-
Abstract: Methods and conjugates are disclosed for alleviating toxicity(ies) associated with administration of immune-stimulatory conjugates, and in particular for alleviating toxicity(ies) associated with intravenous administration of such conjugates.

... read more

Topics: Toxicity (50%)

5 Citations


13 results found

Open accessJournal ArticleDOI: 10.1126/SCITRANSLMED.AAA4306
Abstract: Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligands were formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing cellular cancer vaccines--termed STINGVAX--that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and noncanonical c[A(2',5')pA(3',5')p] phosphate bridge structure, enhanced antitumor efficacy of STINGVAX in multiple aggressive therapeutic models of established cancer in mice. Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8(+) T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmed death ligand 1) up-regulation, which was associated with tumor-infiltrating CD8(+)IFNγ(+) T cells. When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.

... read more

Topics: Stimulator of interferon genes (56%), Interferon gamma (56%), IRF3 (55%) ... read more

429 Citations

Open accessJournal ArticleDOI: 10.1172/JCI86892
Abstract: A major subset of human cancers shows evidence for spontaneous adaptive immunity, which is reflected by the presence of infiltrating CD8+ T cells specific for tumor antigens within the tumor microenvironment. This observation has raised the question of which innate immune sensing pathway might detect the presence of cancer and lead to a natural adaptive antitumor immune response in the absence of exogenous infectious pathogens. Evidence for a critical functional role for type I IFNs led to interrogation of candidate innate immune sensing pathways that might be triggered by tumor presence and induce type I IFN production. Such analyses have revealed a major role for the stimulator of IFN genes pathway (STING pathway), which senses cytosolic tumor-derived DNA within the cytosol of tumor-infiltrating DCs. Activation of this pathway is correlated with IFN-β production and induction of antitumor T cells. Based on the biology of this natural immune response, pharmacologic agonists of the STING pathway are being developed to augment and optimize STING activation as a cancer therapy. Intratumoral administration of STING agonists results in remarkable therapeutic activity in mouse models, and STING agonists are being carried forward into phase I clinical testing.

... read more

Topics: Acquired immune system (59%), Sting (59%), Innate immune system (57%) ... read more

223 Citations

18 May 2014-
Abstract: The present invention provides highly active cyclic-di-nucleotide (CDN) immune stimulators that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the CDNs of the present invention are provided in the form of a composition comprising one or more cyclic purine dinucleotides induce STING-dependent type I interferon production, wherein the cyclic purine dinuclotides present in the composition are substantially pure 2', 5', 2', 5' and 2', 5 ',3 ',5' CDNs, and prefereably Rp,Rp stereosiomers thereof.

... read more

161 Citations

11 Aug 2016-
Abstract: A class of polycyclic compounds of general formula (II), of general formula (II'), or of general formula (II"), wherein Base 1 , Base 2 , Y, Y a , X a , X a1 , X b , X b1 , X c , X c1 , X d , X d1 , R 1 , R 1a , R 2 , R 2a , R 3a , R 4 , R 4a , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , and R 8a are defined herein, that may be useful as inductors of type I interferon production, specifically as STING active agents, are provided. Also provided are processes for the synthesis and use of compounds.

... read more

109 Citations

13 Dec 2013-
Abstract: It is an object of the present invention to provide novel and highly active cyclic-di-nucleotide (CDN) immune stimulators that activates DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the CDNs of the present invention are provided in the form of a composition comprising one or more cyclic purine dinucleotides that induce STING-dependent TBK1 activation, wherein the cyclic purine dinuclotides present in the composition are substantially pure Rp,Rp or Rp,Sp stereoisomers, and particularly substantially pure Rp,Rp, or RpSp CDN thiophosphate diastereomers.

... read more

Topics: Cytoplasmic receptor (54%)

106 Citations

No. of citations received by the Paper in previous years