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Patent

Compounds, compositions, and methods for the treatment of disease

TL;DR: In this article, the authors describe compounds and compositions for the induction of expression of a pattern recognition receptor (e.g., STING) and methods of use thereof, and propose a method of using STING for pattern recognition.
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.
Citations
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Patent
17 Mar 2017
TL;DR: In this article, 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 are discussed.
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.

57 citations

Patent
13 Apr 2018
TL;DR: The present invention relates to anti-SIRPα antibodies, as well as use of these antibodies in the treatment of diseases such as cancer and infectious disease as discussed by the authors, and is related to the use of such antibodies in medical applications.
Abstract: The present invention relates to anti-SIRPα antibodies, as well as use of these antibodies in the treatment of diseases such as cancer and infectious disease

18 citations

Journal ArticleDOI
TL;DR: The cGAS-STING pathway and STing agonists that are in the clinical and preclinical studies are reviewed, recently disclosed patent applications and published journal articles in the field are summarized and both cyclic dinucleotide analogs and non-nucleic acid derived STING agonists are covered.
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.

11 citations

Patent
26 Apr 2018
TL;DR: In this article, the authors presented a method of making the immunoconjugates and methods of treating cancer using the immunocorjugates, including STING agonists, and the methods of making and using them in cancer treatment.
Abstract: Provided herein are immunoconjugates comprising STING agonists. Also disclosed are methods of making the immunoconjugates and methods of treating cancer using the immunoconjugates.

7 citations

Journal ArticleDOI
TL;DR: This review will provide a comprehensive understanding of CDNs based STING agonists on the chemical perspective for readers who are interested in this area.

5 citations

References
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Journal ArticleDOI
TL;DR: For 39 agents with both xenograft data and Phase II clinical trials results available, in vivo activity in a particular histology in a tumour model did not closely correlate with activity in the same human cancer histology, casting doubt on the correspondence of the pre-clinical models to clinical results.
Abstract: An analysis of the activity of compounds tested in pre-clinical in vivo and in vitro assays by the National Cancer Institute's Developmental Therapeutics Program was performed. For 39 agents with both xenograft data and Phase II clinical trials results available, in vivo activity in a particular histology in a tumour model did not closely correlate with activity in the same human cancer histology, casting doubt on the correspondence of the pre-clinical models to clinical results. However, for compounds with in vivo activity in at least one-third of tested xenograft models, there was correlation with ultimate activity in at least some Phase II trials. Thus, an efficient means of predicting activity in vivo models remains desirable for compounds with anti-proliferative activity in vitro. For 564 compounds tested in the hollow fibre assay which were also tested against in vivo tumour models, the likelihood of finding xenograft activity in at least one-third of the in vivo models tested rose with increasing intraperitoneal hollow fibre activity, from 8% for all compounds tested to 20% in agents with evidence of response in more than 6 intraperitoneal fibres (P< 0.0001). Intraperitoneal hollow fibre activity was also found to be a better predictor of xenograft activity than either subcutaneous hollow fibre activity or intraperitoneal plus subcutaneous activity combined. Since hollow fibre activity was a useful indicator of potential in vivo response, correlates with hollow fibre activity were examined for 2304 compounds tested in both the NCI 60 cell line in vitro cancer drug screen and hollow fibre assay. A positive correlation was found for histologic selectivity between in vitro and hollow fibre responses. The most striking correlation was between potency in the 60 cell line screen and hollow fibre activity; 56% of compounds with mean 50% growth inhibition below 10–7.5 M were active in more than 6 intraperitoneal fibres whereas only 4% of compounds with a potency of 10–4 M achieved the same level of hollow fibre activity (P< 0.0001). Structural parameters of the drugs analysed included compound molecular weight and hydrogen-bonding factors, both of which were found to be predictive of hollow fibre activity. © 2001 Cancer Research Campaign www.bjcancer.com

1,448 citations

Patent
18 May 2014
TL;DR: In this article, a cyclic-di-nucleotide (CDN) immune stimulator that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes).
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.

161 citations

Journal ArticleDOI
TL;DR: An integrated set of reactions and conditions that allow an eight-step one-flask synthesis of the protected derivatives of c-di-GMP and the [R(p),R( p)] and [ R(p,S(p)] thiophosphate analogues is reported.

118 citations

Patent
11 Aug 2016
TL;DR: In this article, a class of polycyclic compounds of general formula (II), of general form (II'), or of general condition (II) was defined, which may be useful as inductors of type I interferon production, specifically as STING active agents.
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.

109 citations

Patent
13 Dec 2013
TL;DR: In this paper, a cyclic-di-nucleotide (CDN) immune stimulator that activates DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes).
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.

106 citations

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