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Small molecule sting agonist

small molecule sting agonist The company’s headquarters and laboratories are in Boston, MA with additional operations in Suzhou, China. com. In preclinical studies, MK-1454 improved the responses to a PD-1 inhibitor, supporting its use in combination with immune checkpoint inhibitors. No. Antagonists of the cGAS-STING Pathway The appearance of microbial or aberrant human DNA in the cytosol of cells induces an innate immune response. The report features an in-depth analysis, highlighting the diverse capabilities of stakeholders engaged in this domain May 08, 2019 · NEW DELHI and LONDON, May 8, 2019 /PRNewswire/ --. STING functions as a DNA sensor and induces the  The innate immune system is composed of molecules and cells that respond to As mentioned above, a variety of small-molecule STING agonists promoted  Direct STING agonists are currently in clinical trials in cancer, based on the hypothesis that activation of the STING pathway will trigger antitumor innate immune  27 Jan 2021 The first synthetic human STING agonist is ADU-S100 (Figure 1), which is mimetic of CDN with alternative phosphate bridge and. STING agonist promoted the coordinated and differential cytokine production by dendritic cells, macrophages, and pancreatic cancer cells. In 2017, Nimbus and Celgene forged an agreement to develop Nimbus' small-molecule STING  1 Jan 2019 The foundation for the pursuit of small molecule immune therapies for cancer that apply to TLR agonists are also an issue for STING agonists. Nov 04, 2019 · In contrast, a very recent study reported a novel STING agonist, diABZIs, which is a small molecule developed based on amidobenzimidazole (ABZI) symmetry rather than CDNs that showed strong and systemic antitumor activity in a mouse colon cancer model [ 71 ]. , a leading exosome therapeutics company, announced results from preclinical studies demonstrating the potential of Codiak's proprietary engineered exosome therapeutic, exoSTING. ADU-S100 (MIW815) is a synthetic cyclic dinucleotide agonist of STING, elicits potent and durable anti-tumor immunity when administered IT in pre-clinical syngeneic tumor models. v. The new class of RXFP1 agonists described in J. Med. STING agonist-3 has durable anti-tumor effect and tremendous potential to improve treatment of cancer. PC-62639. In the current report we use human cell lines overexpressing the common R232 variant of STING and cell-free two-protein in vitro kinase assays to demonstrate that G10 is indeed a direct STING agonist. STING has recently emerged as an attractive target in immuno-oncology, though the STING agonists currently in clinical trials are based on high molecular weight cyclic dinucleotide (CDN) scaffolds that possess certain undesirable drug properties. Gao and his team aimed to design a polymer - a manmade macromolecule that can self-assemble into nanoparticles - to effectively deliver cyclic GMP-AMP (cGAMP), a natural small molecule activator of Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. c. Our trial drug, IACS-8803, is a small molecule that mimics the structure of the bacterial DNA and activates STING. 2. Combining innate and adaptive immune responses for better cancer treatment outcomes is the goal. Figure 5. Aug 20, 2020 · Scientists at Scripps Research have discovered a molecule that can activate a natural immune-boosting protein called STING. Details of the presentation are listed below. Potent Anti-Tumor Activity In Mice Following Intravenous Or Oral Administration. 5  8 Feb 2021 "A major limitation of conventional small molecule drugs is that after or first- generation STING agonist approaches that utilize synthetic cyclic  20 Aug 2020 Merck's experimental STING agonist MK-1454 only showed modest efficacy in “Non-nucleotide small-molecule STING agonists that can be  2 Sep 2020 In the same issue of Science, a Scripps Research team described a different oral small molecule STING agonist that was identified via a  13 Mar 2019 With this in mind, the GSK researchers developed a new small-molecule STING agonist that can be given by intravenous injection. (STING) pathway activator derived synthetically which is called a STING agonist. The discovery and characterization of small-molecule antagonists that inhibit the stimulator of interferon genes (STING) protein may help to Natural STING Agonist as an “Ideal” Adjuvant for Cutaneous Vaccination Ji Wang1, Peiyu Li1,3 and Mei X. In view of the unique structure of the high potency Aug 09, 2017 · Conclusion. 8 May 2019 PRNewswire/ -- Curadev today announced it has licensed its novel lead small molecule Stimulator of Interferon Genes (STING) agonist  2 Mar 2018 Concordantly, cGAS–STING agonists, including STING-binding molecules and cGAMP derivatives, have been developed and explored in the  1 Apr 2015 STING agonists have the potential to augment, initiate, or awaken the These small molecules may have value as a monotherapy, delivered in  Here we report the discovery and characterization of highly potent and selective small-molecule antagonists of the stimulator of interferon genes (STING) protein,   27 Apr 2020 Robert L. Meanwhile, there is emphasis on the limitations of these therapies and the future directions required to overcome them, notably the development of novel drug delivery systems (DDS). STING agonist-3 is a selective and non-nucleotide small-molecule agonist of STING with pEC50 and pIC50 of 7. 702662-50-8: G10 (STING Agonist 1) is a novel human-specific STING agonist; triggers IRF3/IFN-associated transcription in human fibroblasts; represenst the first synthetic small molecule characterized as an indirect activator of human STING-dependent phenotypes; inhibits CHIKV replication in vivo. The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer. Can be used in cancer immunotherapy. No. The STING agonist is delivered directly into the tumour Recent advances in the discovery of small molecule inhibitors of Interleukin 1 Receptor-Associated Kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and Nov 23, 2020 · Silicon Therapeutics is currently the only company that owns the entire spectrum of proprietary physics-driven drug discovery from chip-to-clinic. and 6:30 – 8 p. STING Agonist Library is small-molecules that bind and activate STING and lead to IFN production. In 2017, Nimbus and Celgene forged an agreement to develop Nimbus’ small-molecule STING program. STING antagonists offer tremendous potential for new treatments as STING is known to play a role in activating the innate immune system in auto-inflammatory diseases. v. Extensive work with the family A GPCR small molecules, which typically bind to the juxtamem-brane region of their receptors, has shown that trivial chemical modifications of antagonists can convert them into agonists (2). STING Agonist Combo (Cancer) – Pre-Clinical 2018: Preclinical data showing Systemic Small Molecule (STING) driving Tumor Regression. Feb 08, 2021 · Gao and his team aimed to design a polymer - a manmade macromolecule that can self-assemble into nanoparticles - to effectively deliver cyclic GMP-AMP (cGAMP), a natural small molecule activator of Nov 23, 2020 · Silicon Therapeutics is currently the only company that owns the entire spectrum of proprietary physics-driven drug discovery from chip-to-clinic. identified a non-nucleotide, small-molecule STING agonist (SR-717) that activated STING by inducing a closed conformation similar to cGAMP. com Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. ” "A major limitation of conventional small molecule drugs is that after injection into tumors, they are washed out from the tumor site by blood perfusion, which can reduce antitumor efficacy while Dec 31, 2020 · To boost accumulation of Th17 and Tc17 cells near solid tumors, they turned to two small molecules that can activate an immune response: the stimulator of interferon genes (STING) agonists DMXAA AHR 1 Small Molecule n Anti-TIGIT 1 Biologic Anti-ICOS 1 Biologic NLRP3 Agonist 1 Small Molecule n Anti-IL8 1 Biologic n Anti-TIM3 1 Biologic Anti-CD73 1 Biologic STING Agonist 1 Small Molecule n EP4 Antagonist 1 Small Molecule n Anti-CTLA-4 NF 2 Biologic Anti-CTLA-4 Probody 2 Biologic n CCR2/5 Dual Antagonist 2 Small Molecule Marizomib 3 Small Sep 19, 2020 · STING links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. summary: novel, small molecule direct sting agonists activating sting pathway in both mouse and human immune cells the compounds show good selectivity and in vitro adme properties enabling further development and in vivo efficacy studies cmpd 1 and cmpd 2 bind to hsting cmpd 1 and 2 thermally stabilize human sting wt protein Mar 13, 2019 · With this in mind, the GSK researchers developed a new small-molecule STING agonist that can be given by intravenous injection. Meanwhile, Mavupharma isn’t the only company trying to develop small-molecule STING agonists. But one polymer they synthesized, PC7A, produced an unexpected and novel effect: It activated STING even without The Aduro-proprietary STING pathway activator product candidates, including ADU-S100 (MIW815), are synthetic small molecule immune modulators that are designed to target and activate human STING. m. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. STING agonist-3 has durable anti-tumor effect and tremendous potential to improve treatment of cancer. Dec 01, 2020 · The drug candidate SB-11285 is a small molecule-nucleic acid hybrid STING agonist developed by Spring Bank Pharmaceuticals for the potential treatment of cancer and viral infections. 4 Sep 2020 Furthermore, we will review cGAS-STING agonist delivery systems II study in untreated patients with advanced non-small cell lung cancer  STING is a key cytosolic receptor for small nucleotides and plays a key role in non-nucleotide small-molecule STING agonist with a pEC50 and pIC50 of 7. Recent findings are beginning to elucidate a potential shortcoming of smSTING agonists in that they may lead to activation of STING in “off- A detailed assessment of the current market landscape of therapeutics targeting STING pathway, based on several parameters, such as type of STING modulator (agonist or antagonist), type of molecule (small molecules, cyclic dinucleotides, non-nucleotides, biologics and others), phase of development (discovery, preclinical and clinical), target therapeutic area(s), type of therapy (monotherapy and combination therapy), route of administration (intratumoral, intravenous and others), and line of STING Agonist-1. , Co-Founder & CSO, Spring Bank Pharmaceuticals Immunotherapy has emerged as a transformative approach for the treatment of cancer. , President and CEO, Progenra, Inc. J. candidates for inhibition of protein-protein interactions with respect to conventional small molecules. Small Molecules for Immunology, Oncology and COVID on May 19-20 explores drug candidates that have the potential to be orally bioavailable modulators of the immune system. Hence, we investigated the ability of a recently discovered small molecule STING agonist, dimeric amidobenzimidazole (diABZI) to circumvent the BRAFi-resistance developed by melanoma cells. Spring Bank’s lead clinical STING agonist is SB 11285, a second generation, intravenously-administered immunotherapeutic agent for the treatment of certain cancers. Purity & Quality Control PO-424 Discovery of a novel small molecule sting agonist as a new cancer immunotherapy. MK-1454 is an investigational small molecule STING agonist administered as an intratumoral injection that is currently being evaluated in a Phase 1 clinical trial for the 2 Small molecule agents (as opposed to biologics) that steer or enable the immune system to attack cancer cells represent an emerging area of R&D focus in the oncology drug development industry. STING agonist-3, extracted from patent WO2017175147A1 (example 10), is a selective and non-nucleotide small-molecule STING agonist with a pEC and of 7. STING Agonist. 8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) mimetic Herein, we describe the discovery of highly potent and selective first-in-class STING agonist SB 11285 for application in immuno-oncology. Aug 21, 2020 · “Non-nucleotide small-molecule STING agonists that can be administered systemically may represent an attractive approach for targeting this path­way and have the potential to transform the therapeutic landscape once optimized,” wrote two University of Chicago scientists in a related Perspective in Science. 96% Clinical Data:No Development Reported Size: 5 mg, 10 mg, 25 mg STING agonist-4 Cat. In partnership with Celgene, the company is developing a STING agonist for autoimmune disorders. “Finding ways to package a STING agonist so it can be given systemically, yet still mostly accumulate in tumors, will be an important next step. IMQs, including imiquimod and resiquimod (R848), are by far the In this presentation, we report a novel small molecule STING antagonist that inhibits constitutive and STING agonist-induced type I IFN expression in vitro in wild-type, as well as, GOF STING The use of small molecule STING agonists has yielded mixed results. 5 and 9. Therefore, STING agonists are regarded as promising immune adjuvants for promoting immune responses against tumors and infections. Jul 04, 2018 · Here we report the discovery and characterization of highly potent and selective small-molecule antagonists of the stimulator of interferon genes (STING) protein, which is a central signalling Here we report the discovery and characterization of highly potent and selective small-molecule antagonists of the stimulator of interferon genes (STING) protein, which is a central signalling component of the intracellular DNA sensing pathway 1,2. According to these authors, SR-717 demonstrated robust anti-tumor activities in a mouse model of melanoma. Details on Chin et al. Butt, Ph. 5 and 9. 5 and 9. ) efficacious non-CDN STING agonist with systemic anti-tumour activity in murine models. NPYLR7 CRISPR-Cas9 null mutants are defective in behavioral suppression and resistant to these drugs. Specifically, we showed that BNBC induced type I and III IFN dominant cytokine responses in primary human fibroblasts and peripheral-blood mononuclear cells (PBMCs). Priming and activation of a potent T cell mediated anti-tumor adaptive response. Chin et al. Merck is exploring the role of the STING pathway across a variety of tumors as monotherapy and in combination with the company’s anti-PD-1 therapy, KEYTRUDA. Product Name. In the case of MSA-2, the monomer is not available to bind STING, whereas the non-covalent pre-dimerization of MSA-2 induced STING binding and Feb 11, 2019 · IFM Due, a subsidiary of IFM Therapeutics, is a biopharmaceutical company developing a suite of small-molecule antagonists and inhibitors targeting aberrant inflammatory responses of the innate immune system triggered by the cGAS-STING pathway, which is believed to underlie a variety of serious diseases. GlaxoSmithKline is also working in this area, for example, and in a high-throughput screening programme has discovered a number of small-molecule candidate, headed by GSK3745417, but so far these can only be delivered intravenously or subcutaneously. Endogenous STING and DDX41 agonist; activates STING-dependent signaling. May 08, 2019 · A poster presented at the 2019 Annual Meeting of the American Association for Cancer Research (LB-061: "CRD5500: a versatile small molecule STING agonist amenable to bioconjugation as an ADC AR-LDD 1 Small Molecule n CD3xPSCA (GEMoaB)+ 1 Biologic n IL-12 Fc 1 Biologic n Motolimod 1 Small Molecule n NLRP3 Agonist 1 Small Molecule n STING Agonist 1 Small Molecule n TGFβ Inhibitor 1 Biologic n LSD1 inhibitor * 2 Small Molecule n Anti-CTLA-4 NF 2 Biologic Anti-CTLA-4 Probody 2 Biologic n CCR2/5 Dual Antagonist 2 Small Molecule On November 6, 2018, Codiak BioSciences, Inc. Preclinical studies suggest that treatment with E7766 by Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA 1. Sep 24, 2020 · In a detailed report in Science, Chin and colleagues described using a cell-based phenotypic screening approach to identify functioning non-nucleotide small molecule STING agonists. STING appears to be a dimer, with 398 and 378 amino acids in humans and mice, respectively. Conference: Abstracts of the 25th Biennial Congress of the European Association for Cancer Research the development of cyclic dinucleotide (CDN) and non-nucleotidyl small-molecule STING agonists and their preclinical and clinical trials as cancer immunotherapies. The development of compounds that modulate STING has recently been the focus Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. Apr 29, 2019 · Further, STING agonist treatment upregulated costimulatory molecule expression on cross-presenting dendritic cells and reprogrammed immune-suppressive macrophages into immune-activating subtypes. ADU-S100  View our 6 STING Agonists Small Molecules for your research. 2019: $35 Million Series B Trillium’s AACR presentation described TTI-10001, a novel small molecule STING agonist that exhibits favorable potency, cell permeability, and tumor retention properties that could potentially The STING protein, discovered in 2008, helps mediate the body’s innate immune system – the collection of immune molecules that act as first responders when a foreign agent circulates in the body, The elements of this pharmacophore were incorporated into nonpeptidic small-molecule scaffolds, resulting in lead compounds disrupting CD47/SIRPα interaction. Nov 07, 2018 · Codiak’s data highlight the unique profile of exoSTING, where the STING agonist is selectively delivered to tumor-resident APCs by using Codiak’s precision exosome platform to leverage the natural biology of exosomes, which carry macromolecules between tumor and immune cells. The lead CD47 antagonists induced phagocytototic activity of human macrophages to a similar extent as commercially available anti-CD47 antibodies. In relation to TLR7 and TLR8, synthetic small molecule TLR7/8 agonist–based adjuvants include synthetic chemical agonists such as imidazoquinolines (IMQs) (33–35) and benzazepines . The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer. Jul 16, 2019 · Industry watchers will recall that only a month ago Takeda, which separately has an in-house Sting agonist, TAK-676, licensed Curadev’s CRD5500, a small-molecule Sting activator said to be amenable to development as an antibody-drug conjugate. 5900. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. “Celgene is committed to the continued growth of our Activation of STING using small molecules is a novel therapeutic approach gaining significant traction in the translational immuno-oncology research community. ABSTRACT: Identification of covalent small-molecule inhibitors of STING Overall design: Primary wild-type Bone Marrow Derived Macrophages were treated either with Sting inhibitor or Sting agonist (CMA) or inhibitor and CMA together for 2h. For research use only. Based on these findings, GSK are undergoing a Phase I clinical trial looking at a diABZI-like molecule GSK3745417 (Section 6. But one polymer they synthesized, PC7A, produced an unexpected and novel effect: It activated STING even without Nov 06, 2019 · The meeting will be held November 6-10 in National Harbor, MD. J Exp Med, EPub: December 5, 2014. 5945) are cyclic nucleotides and aim to activate an immune response in the tumor microenvironment. While existing drugs activate the protein over the course of about six hours, PC7A forms polyvalent condensates with STING for over 48 hours, causing a more sustained effect on quest for small molecule leads for its internal STING agonist program. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4532A. 50 pIC 50 Purity: 99. Aug 20, 2020 · “Non-nucleotide small-molecule STING agonists that can be administered systemically may represent an attractive approach for targeting this path­way and have the potential to transform the The most promising non-nucleotidyl small molecule STING agonist is diABZI, the first intravenous (i. Nov 17, 2020 · This study focuses specifically on small molecule STING modulators. Since the first-generation murine STING agonist, DMXAA, was developed as an anti-angiogenic agent, 13 we sought to determine whether delivery of low-dose ADU S-100 would support VN via a paradigm originally proposed by Jain et al, 6 leading to increased production of antiangiogenic factors within the treated TME. Clinical trials other hand, the approach targeting much ‘small’ molecule discovered a new orally available STING agonist, MSA-2, by phenotypic screening for chemical inducers of IFNβ secretion (Figure 1) [32]. The company has a wholly-owned STING agonist for use in immuno-oncology. By screening a large small-molecule library, Pan et al. Mar 14, 2019 · Nimbus is developing a couple of STING agonists. purity CMA. However, it was recently discovered that many mammalian cell types express cGAMP importers on the plasma membrane that directly import cGAMP from extracellular space to the cytosol Apr 27, 2017 · 1:05 Development of SB 11285, a Highly Potent STING Agonist for Application in Immune-Oncology R. For example, among three amidobenzimidazole (ABZI)-based small-molecule STING agonists reported in the same study, the most potent compound was shown to bind several human isoforms and one murine isoform of STING with high affinity, inducing dose-dependent activation of STING and secretion of IFNβ in human PBMCs, and its intravenous delivery strongly reduced subcutaneous CT-26 colon tumor growth in mice STING (inhibitors, antagonists, agonists)-ProbeChem. The poster presentation will highlight the anti-tumor activity of TTI-10001, a novel small molecule STING agonist, when delivered intravenously or orally. First, they  20 Aug 2020 describe SR-717 - a stable, non-nucleotide small molecule STING agonist that functions similarly to the natural STING ligand cGAMP. But one polymer they synthesized, PC7A, produced an unexpected and novel effect: It activated STING even without cGAMP. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. describe SR-717 - a stable, non-nucleotide small molecule STING agonist that functions similarly to the natural STING ligand cGAMP. Nov 05, 2018 · MK-1454 is a small molecule activator (agonist) of STING being developed by Merck for a variety of tumors. Their lead Mouse STING agonist Small molecule Stability-enhanced natural agonist Cyclic dinucleotide Human / multi-species active 0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 1 0 A poster presented at the 2019 Annual Meeting of the American Association for Cancer Research (LB-061: "CRD5500: a versatile small molecule STING agonist amenable to bioconjugation as an ADC") reported that the Curadev STING agonist potently activates all major known human STING variants and activates the immune system to shrink distant tumors and combines well with anti-PD-L1/anti-CTLA4/IDO-TDOi when dosed IT or systematically. Natural and synthetic CDNs as direct STING agonists. Moreover, new generation of developed agonists show signifi- Stimulator of interferon genes (STING) is an integral ER-membrane protein that can be activated by 2'3'-cGAMP synthesized by cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) upon binding of double-stranded DNA. Here, we report that a natural agonist of stimulator of interferon In the new paper, Gao's team showed that PC7A binds to a different site on the STING molecule from known drugs. Oct 31, 2018 · the poster presentation entitled: “Novel class of small molecule direct STING agonists as potential cancer immunotherapy”, abstract no. Information. ” “A 1. The development of compounds We have designed and developed potent classical small molecule (non-nucleoside) human STING agonists that activate all isoforms of human STING leading to robust secretion of Type I interferons and related cytokines. Murine-selective STING agonist. Moreover, its effect on the STING protein is different. We have previously demonstrated that TTI-10001, a novel non-cyclic dinucleotide (CDN) small molecule STING agonist with pan-allele STING activity and ideal drug properties, potently induces the STING pathway in vitro and results in robust anti-tumor activity in vivo following intratumoral (IT) administration. STING (Stimulator of Interferon Genes) is an innate immune sensor of aberrant cytosolic dsDNA, and its activation by binding to ligand bridges the innate immunity and adaptive T cell response. The use of an NLRP3 agonist may be an excellent strategy to provoke inflammation and attract cells of the immune system into the tumor environment – then, using a STING agonist to activate the dendritic cells would set-up the first step in an adaptive immune response. , Hall E CRANBURY, N. 10,11 Investigators also are exploring small molecule PPR agonists, it did not reveal any information about antagonist compounds. exoSTING is composed of precision engineered exosomes loaded with a potent small molecule STING (stimulator of interferon genes) agonist. We show that pharmacological activation of STING using diABZI downregulates NRF2-dependent antioxidative responses thereby sensitizing melanoma cells to BRAFis. Ferris, MD, PhD, discusses the rationale for evaluating STING agonists as treatment for patients with head and neck cancers. D. Fragments of this DNA bind to the cytosolic DNA sensor cGAS, which catalyzes the synthesis of the second messenger 2′3′-cGAMP, which in turn triggers STING-dependent interferon production and "A major limitation of conventional small molecule drugs is that after injection into tumors, they are washed out from the tumor site by blood perfusion, which can reduce antitumor efficacy while H-151 (941987-60-6) is an inhibitor of the signaling molecule STING in mouse and human cells. However, early-phase clinical trials of small-molecule STING agonists have shown limited antitumour efficacy and dose-limiting toxicity. 5, respectively. Oct 27, 2019 · The SiTX lead program is a small molecule STING agonist for systemic delivery in I/O that is slated to enter the clinic in mid-2020. However, early-phase clinical May 18, 2020 · Provectus Announces PV-10® STING Agonist Abstract at American Association for Cancer Research (AACR) 2020 Virtual Annual Meeting II is a small molecule halogenated xanthene and PV-10’s We have commenced a drug discovery program in collaboration with the Blumberg Institute to identify potent, orally active small molecule human STING agonists that possess the desired characteristics to progress into human clinical studies. In summary, our work uncovers a mechanism by which STING can be inhibited pharmacologically and demonstrates the potential of therapies that target STING for the treatment of autoinflammatory disease. Alzabin, S. 4. Because small molecule drug candidates have oral bioavailability, they offer greater patient convenience and are being explored as potential stand-alone therapies to replicate the success of the recent Annotated Bibliography Silicon Therapeutics Presents Preclinical Data Showing a Systemic Small Molecule Sting Agonist Drives Tumor Regression Through a Potent Anti-tumor Immune Response-small-molecule-sting-agonist-drives-tumor-regression-through-a-potent-anti-tumor-immune-response/ Data Presented at AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference In this press conference Activation of the stimulator of interferon gene (STING) has emerged as an exciting immuno-oncology therapeutic strategy; however, the first-generation STING agonists, cyclic dinucleotide (CDN) analogues, have suffered from many disadvantages and failed in clinical trials. It reduced systemic cytokine response in mice treated with the STING agonist 10-carboxymethyl-9-acridanone and showed efficacy in Trex -/- mice. STING agonist-1 (G10) STING agonist-1 (G10) is a novel human-specific STING agonist that triggers IFN regulatory factor 3 (IRF3)/ type I interferon (IFN)-associated transcription in human fibroblasts. STimulator of Interferon Genes (STING) is a master regulator of type I interferons and a key mediator of innate immunity. Wu1,2 A potent adjuvant that induces strong protective immunity without incurring any significant skin reactogenicity is urgently needed for cutaneous vaccination. CAS No. CRD5500 is a small molecule STING agonist that can be delivered in multiple formats making it well suited for further development as an anti-cancer agent. ) efficacious non-CDN STING agonist with systemic anti-tumour activity in murine models. The process is expected to use the tumor itself as a “vaccine,” Nov 06, 2019 · The meeting will be held November 6-10 in National Harbor, MD. identified an orally available small-molecule STING agonist (MSA-2), which bound to mouse and human STING as a noncovalent dimer and exhibited higher cellular potency in an acidified tumor microenvironment. The company’s headquarters are located in Boston. 2,3 Dec 01, 2020 · Small molecule agonists targeting STING Activation of STING is associated with biological Using DMXAA—the mouse-specific STING agonist—as a starting point for developing small molecules has been “very successful” so far, Nicholson says. 2:20 Small Molecule Ubiquitin Protease (USP7) Inhibitors with Immune Cell Based Anti-Tumor Activity Superior to that of Biologicals Tauseef R. , Hematopoietic progenitor kinase 1 is a negative regulator of dendritic cell activation (2009). Aug 25, 2020 · “From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. Meanwhile, Mavupharma isn’t the only company trying to develop small-molecule STING agonists. The company’s lead program is a highly differentiated small molecule Stimulator of Interferon Genes (STING) agonist for the treatment of cancer. The poster presentation will highlight the anti-tumor activity of TTI-10001, a novel small molecule STING agonist, when delivered intravenously or orally. 1. Stimulator of interferon genes (STING) is a signaling molecule that plays a crucial role in controlling the transcription of many host defense genes, including proinflammatory cytokines and - chemokines, and type I interferons (IFNs) [1, 2]. Sep 05, 2019 · One is aimed at developing oral small-molecule antagonists of STING that can block its ability to stimulate excessive production of interferons and other pro-inflammatory cytokines. silicontx. 1 STING functions as a DNA sensor and induces the production of IFNβ by tumor-associated stromal cells, leading to the activation of dendritic cells (DCs), thereby driving T-cell priming and recruitment into the tumor microenvironment. Aug 25, 2020 · “From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. Our small molecule agonist rapidly activates the STING/TBK1/IRF3 pathway (phosphorylation and translocation) and induces the expression of type I IFN in cells in a STING-dependent manner. In vitro GDP/GTP exchange assay reveals that KRA-533 activates KRAS by preventing the cleavage of GTP into GDP, leading to the accumulation of GTP-KRAS, an active form of KRAS. According to these authors, SR-717 demonstrated Results Ryvu’s small-molecule agonists demonstrate strong binding affinity to recombinant STING proteins across all tested species. 38609-97-1 | STING Agonists Rep. STING is Jul 05, 2018 · Furthermore, we show that these small-molecule antagonists attenuate pathological features of autoinflammatory disease in mice. 01 μM and blocks replication of Alphavirus species Aug 06, 2019 · The company is also developing its lead STING agonist product candidate, SB 11285, an immunotherapeutic agent for the treatment of selected cancers. However, the efficacy of small molecule STING agonists as vaccine adjuvants may be limited because they are rapidly cleared and may not gain long-lived access to the cytosol for STING activation. 5 and 9. May 18, 2020 · Rose bengal (RB) disodium (4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein disodium salt) is a small molecule halogenated xanthene and PV-10’s active pharmaceutical ingredient. 1638750-95-4. The company is developing its STING product portfolio with its lead clinical product candidate, SB 11285, an intravenously-administered immunotherapeutic agent for the treatment of selected cancers, its STING antagonist compounds for the treatment of a broad range of inflammatory diseases and its STING agonist ADC program for potential oncology Nov 23, 2020 · SNX281 is a novel systemically available small molecule agonist of Stimulator of Interferon Genes (STING) and the company’s first investigational candidate to enter the clinic Posted by Silicon Therapeutics Silicon Therapeutics Announces Dosing of First Patient in Phase 1 Open-Label Clinical Trial of SNX281 for Advanced Solid Tumors or Lymphoma STING agonists, including 2’,3’-cGAMP (Cat. Mechanistically, the identified compounds covalently target the predicted transmembrane cysteine residue 91 and thereby block the activation-induced palmitoylation of STING. According  Our STING agonist* is a small molecule that binds to the stimulator of interferon ( IFN) genes (STING). 2′,3′-cGAMP is an endogenous high-affinity STING agonist. However, cyclic di-GMP (cdGMP) injected s. STING agonist-3, CAS 2138299-29-1 Bulk Size: Please Quote for Discount Add to Cart Apr 10, 2019 · Here we identified a small molecule KRAS agonist, KRA-533, that binds the GTP/GDP-binding pocket of KRAS. Therefore, non-CDN small-molecule STING agonists are urgently needed. Development of selective small molecule STING agonists suitable for systemic administration [abstract]. Apr 02, 2019 · STING (stimulator of interferon genes) is an adaptor protein involved in sensing cytosolic DNA that plays a key role in promoting tumor immunity. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. While existing drugs activate the protein over the course of about six hours, PC7A forms # polyvalent # condensates with STING for over 48 hours, causing a more # sustained Among this month’s highlights are a small molecule with twice-a-year dosing from Gilead, a non-classical C-H—O hydrogen-bonding kinase inhibitor from Pfizer, an E1 ligase inhibitor with a cool substrate-assisted covalent mechanism from Takeda, and some STING agonists with well-tolerated oral activity and Read more… Nimbus will continue to own and develop its small-molecule STING agonist program for immuno-oncology, which is not part of the agreement. 8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) mimetic that induces the same ‘closed’ conformation of STING. Small molecule drug conjugates or SMDCs are built with three modules: a targeting ligand, a linker and a drug payload. No. In the new paper, Gao's team showed that PC7A binds to a different site on the STING molecule from known drugs. Moreover, its effect on the STING protein is different. 8 Dec 2020 This study focuses specifically on small molecule STING modulators. Intra-tumoral injection of the STING agonist ADU-S100 is currently under investigation in phase 1 clinical trials (Toogood, 2018). In summary, our work uncovers a mechanism by which STING can be inhibited pharmacologically and demonstrates the potential of therapies that target STING for the treatment of autoinflammatory disease. Emerging alphaviruses are sensitive to cellular states induced by a novel small- molecule agonist of the STING pathway. Learn more at www. While the intended target is antigen-presenting cells (APCs), at high doses these agonists often lose efficacy 7 as they may also Aug 20, 2020 · A small molecule that activates the immune protein STING shows promising results against tumors in preclinical tests. HT1376 human bladder cancer cells were plated. The value of that deal, too, was kept under wraps. ” “A 1. , March 10, 2021 (GLOBE NEWSWIRE) -- PMV Pharmaceuticals, Inc. 110 Although active in mice, the compound was found to bind to the human STING without activation and failed in a phase III clinical trial in combination with Our STING agonist is a small molecule that binds to the stimulator of interferon (IFN) genes (STING). J. SR-717 induced IFNB1, CXCL10, and IL6 expression and phosphorylation of TBK1, IRF3, and p65 downstream of STING in THP1 cells in vitro. SR-717 displays antitumor activity, promotes the activation of CD8 + T, natural killer, and dendritic cells in relevant tissues; and facilitates antigen cross-priming. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING STING is normally stimulated by the presence of bacterial DNA, and it, in turn, increases the production of local signals that increase tumor-fighting immune cell activity. 5, respectively. Journal of Oct 16, 2020 · The most promising non-nucleotidyl small molecule STING agonist is diABZI, the first intravenous (i. 1. ” Mavupharma has set its sights on this route, with plans to develop non-nucleotide small molecules that, delivered orally, modulate the STING pathway indirectly rather than target the receptor itself. Cat. P515, will take place on Friday, November 9, between 12:45 – 2:15 p. Aug 20, 2020 · Chin et al. Dec 08, 2015 · This enabled identification of the STING protein as required for G10’s biological activity thus indicating that the compound is the first described human-specific synthetic small molecule STING agonist. Curadev today announced it has licensed its novel lead small molecule Stimulator of Interferon Genes (STING) agonist (referred to by Curadev as May 08, 2019 · LONDON, May 8, 2019 /PRNewswire/ -- Curadev today announced it has licensed its novel lead small molecule Stimulator of Interferon Genes (STING) agonist (referred to by Curadev as CRD5500) and May 09, 2019 · “CRD5500 is a small molecule STING agonist that can be delivered in multiple formats making it well suited for further development as an anti-cancer agent. ADU-S100. Activation of STING provides two critical anti-tumor responses: The “spark” for initiating a robust innate immune response. We report herein a compound, 6-bromo-N-(naphthalen-1-yl)benzo[d][1,3]dioxole-5-carboxamide (BNBC), that induces a proinflammatory cytokine response in a human-STING-dependent manner. INSTRUMENT (S): Illumina NextSeq 500 (Mus musculus) May 19, 2020 · STING is a protein that has the potential to activate the body’s innate immune system in the presence of cancer. PV-10 drug product is a formulation of 10% w/v RB in 0. Treatment of primary immune cells from healthy human donors results in the activation of dendritic cells and upregulation of costimulatory markers. Aug 21, 2020 · The first STING agonist investigated for immunotherapy was the molecule DMXAA, which had antitumor activity in preclinical models and was subsequently determined to interact with the mouse STING molecule but not human STING . 5, respectively. receptor antagonist (preclinical drug candidate to be selected in Q120), small molecule STING agonist for systemic administration, an HPK1 inhibitor and first-in- class SMARCA2 inhibitor for treating SMARCA4 mutated cancers. While the first wave of STING agonists are derived from cyclic dinucleotides limited to intra-tumoral delivery, we discovered a small molecule dimeric ligand known as the ABZI series that is selective STING agonists with remarkable single agent efficacy upon intravenous delivery. E7766 is a STING agonist with broad specificity to all major genetic variants of human STING 13. : HY-123943 STING agonist-4 is an stimulator of Interferon May 14, 2020 · We hypothesized that activation of NRF2 in BRAFi-resistant melanoma cells could be the cause of diminished STING-activity. The company’s lead program is a highly differentiated small molecule Stimulator of Interferon Genes (STING) agonist for the treatment of cancer. We previously reported a cell-based high-throughput-screening assay that allowed for identification of small-molecule cGAS–STING-pathway agonists. Guiding selective STING/TLR agonists to specific target sites in solid tumors using ADC, mRNA, Exosome-based and small molecule technologies described by Bolt Biotherapeutics, AstraZeneca, Codiak Biosciences, Ryvu Therapeutics and more. et al. Preclinical and  14 Mar 2019 STING agonist for use in immuno-oncology. August 20, 2020 LA JOLLA, CA — Scientists at Scripps Research and Calibr, the institute’s drug discovery division, have discovered a molecule that can activate a natural immune-boosting protein called STING to help patients exoSTING is a precision engineered exosome therapeutic candidate that is surface engineered with the protein PTGFRN, and luminally loaded with a proprietary, potent small molecule STING (stimulator Small molecule STING (smSTING) agonists are of particular interest because of their role in the production of type I interferons (IFNs) and the subsequent generation of antitumor immunity5–7. NKTR-262 is a novel small molecule agonist designed to activate toll-like receptors (TLRs). (Nasdaq: PMVP), a precision oncology company pioneering the discovery and development of small molecule, tumor-agnostic therapies targeting p53 mutants, today announced that the company will present at the American Association for Cancer Research (AACR) Annual Meeting 2021 taking place April 10-15, 2021. It could cause STING-dependent inductions of IRF and NF- κ B with EC 50 values of 2 and 200 nmol/L, respectively, which were at least 200-fold more potent than 2 ′ ,3 ′ -cGAMP. , 2015;5:18035; Targeting STING with covalent small-molecule inhibitors. G10 triggers innate immune responses that involve expression of IRF3-dependent genes including type I and III interferons. The formu- lation of the sensitizers consisted in a 1 mg/   26 Feb 2018 Thus many small firms are racing to develop and test the first small-molecule STING agonists that could be injected systemically or taken via pill  2 Sep 2019 As discussed above, small molecule STING agonists as well as cytosolic DNA species can stimulate the STING signaling pathway to promote  4 Mar 2019 Box 1 STING agonists struggle to match the human cancer hype IFM Due, recently reported on a series of small-molecule STING antagonists,  TTI-10001, A Next Generation Small Molecule STING Agonist, Demonstrates. Based on these findings, GSK are undergoing a Phase I clinical trial looking at a diABZI-like molecule GSK3745417 (Section 6. 5) (NCT03843359). 92(6), e01913-01917 (2018). 9% saline, supplied in single-use glass vials containing 5 mL (to deliver) of solution, and STING agonist-3, extracted from patent WO2017175147A1 (example 10), is a selective and non-nucleotide small-molecule STING agonist with a pEC50 and pIC50 of 7. Mouse and human STING proteins are fairly similar, except for the spot where a CDN or small molecule binds. 5, respectively), has durable anti-tumor effect and tremendous potential to improve treatment of cancer. DMXAA is a cell-permeable small-molecule agonist of STING, whereas CDN agonists are negatively charged and thus nonpermeable to cell membrane. It covalently binds to Cys91 of STING preventing activation via blockade of palmitoylation at Cys91. 2020年11月1日 providing effective clues and correct guidance for the discovery of novel small molecule inhibitors/agonists that targeted STING for cancer,  Background: Apatinib, is a novel, small molecule, selective VEGFR-2 TKI and is approved in China as third-line treatment for patients with AGC. describe SR-717 - a stable, non-nucleotide small molecule STING agonist that functions similarly to the natural STING ligand cGAMP. Curadev’s small molecule STING antagonist program aims to discover and develop inhibitors of the intracellular stimulator of interferon genes (STING) pathway, which can modulate Trillium Therapeutics Inc. STING agonist-1 (G10) potently reduces growth of Chikungunya virus (CHIKV) with IC90 of 8. For more information, please visit www Feb 08, 2021 · Gao and his team aimed to design a polymer – a manmade macromolecule that can self-assemble into nanoparticles – to effectively deliver cyclic GMP-AMP (cGAMP), a natural small molecule activator of STING, to the protein target. Methods: We used a pharmacophore based approach to identify small molecule human STING agonists. It activates interferon (IFN) and inflammatory cytokine responses to defend against infection by microorganisms. Using their physics-driven discovery engine, plus cutting-edge capabilities in biology, chemistry, and biophysics, Silicon Therapeutics has developed small molecule agonists of STING that exhibit activity across all known isoforms of the human protein. Feb 07, 2019 · To obtain small-molecule agonists selective for NPYLR7, we performed a high-throughput cell-based assay of 265,211 compounds and isolated six highly selective NPYLR7 agonists that inhibit mosquito attraction to humans. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and For example, both iTeos Therapeutics and Nimbus Therapeutics have a STING program developing small-molecule agonists that have improved drug properties. (Nasdaq/TSX: TRIL), a clinical-stage immuno-oncology company developing innovative therapies for the treatment of cancer, today announced that it has expanded its immuno-oncology pipeline with a STING agonist program and presented preclinical data from this program at the 2019 Annual Meeting of the American Association for Cancer Research (AACR). P. Jan 30, 2019 · Also, small molecule agonists against STING—a protein that ramps up production of interferons and cytokines—are major targets on the radar for therapeutic development, as well as molecules that target Toll-like Receptors (TLRs) and RIG-I-like Receptors (RLRs). Small molecule API development services to speed your molecule through early phase trials and prepare you for commercial success, faster. Gao and his team aimed to design a polymer — a manmade macromolecule that can self-assemble into nanoparticles — to effectively deliver cyclic GMP-AMP (cGAMP), a natural small molecule activator of STING, to the protein target. First, they used high-throughput screening as a technique to search among millions of small molecules, hoping to find some that bind to STING and regulate its activity. The STING agonist is a small molecule that when injected directly into a tumor can stimulate an immune response against the components of the tumor. TTI-10001 is a novel, non-CDN, potent, small molecule pan-STING agonist TTI-10001 exhibits favorable potency, cell permeability, and tumor retention properties that could potentially overcome the common limitations of current CDN-derived STING agonists TTI-10001 is well tolerated in mice at relevant doses after IT or IV administration In a Nature paper, the GSK team identified a small molecule, amidobenzimidazole, that outcompeted STING's natural ligand, cyclic GMP-AMP (cGAMP), for binding to the receptor. The structurally unrelated STING activator vadimezan ( 47 , University of Auckland/Novartis) showed an immune‐mediated antitumor response in mice. m. D. The findings mark a key advance in the field of oncology, as the STING Nov 09, 2018 · Aduro Biotech has reported its first data for STING agonist ADU-S100, hoping to rebuild confidence in the mechanism after lackluster data from Merck last month. Intratumoral, subcutaneous, and orally administered MSA-2 induced interferon-β Oct 03, 2017 · The alliance also covers Nimbus’ preclinical small-molecule STING (stimulator of interferon genes) antagonist program, which seeks to block the role played by STING in the activation of the innate immune system in lupus and other interferonopathies. 1. A dimeric compound Nov 07, 2018 · Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA 1. We PLOS ONE G10 directly activates human STING The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer. Gao and his team aimed to design a polymer – a manmade macromolecule that can self-assemble into nanoparticles – to effectively deliver cyclic GMP-AMP (cGAMP), a natural small molecule activator of STING, to the protein target. The company’s headquarters are located in Boston. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. Virol. The compounds bind to all human STING pro-tein variants and trigger pro-inflammatory cytokine release from human immune cells regardless of the STING haplotype. STING agonist-3 is a selective and non-nucleotide small-molecule STING agonist (pEC50 and pIC50 of 7. Our STING agonist* is a small molecule that binds to the stimulator of interferon (IFN) genes (STING). The targeting ligands consist of low   Full agonists are opioid drugs that bind to mu opioid receptors in the brain, and cause When the dosage of a partial agonist is increased, there is only a small  and Chair of the Department of Pharmacology, Professor of Molecular and Integrative One of the limitations of this model is that there's such a small window  . 1. (Kris) Iyer, Ph. The first generation of human STING agonists, including MIW815 (ADU-S100) and MK-1454, have been investigated in early Small‐molecule STING agonists. Jul 01, 2018 · Small molecule agonist families have been identified which activate TLR2, TLR4, TLR7, and TLR8. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) -stimulator of interferon genes (STING) signaling pathway is the primary  1 Dec 2019 Abstract LB-A20: True small molecule STING agonist generates systemic and potent anti-tumor immunity required for effective cancer  STimulator of Interferon Genes (STING) is a master regulator of type I the novel small molecule STING agonist (SNX281) with excellent drug properties  16 Oct 2020 Keywords: cGAS; STING; immune checkpoint inhibitors (ICI); cyclic dinucleotides (CDNs); small molecule agonist; STING agonists; immune  Material and methods A375 human melanoma cells and. 5) (NCT03843359). However, early-phase clinical trials of small-molecule STING agonists have shown limited antitumour efficacy and dose-limiting toxicity. are also actively evaluating multiple STING agonists/antagonists. We do not sell to patients. Details of the presentation are listed below. GlaxoSmithKline is also working in this area, for example, and in a high-throughput screening programme has discovered a number of small-molecule candidate, headed by GSK3745417, but so far these can only be delivered intravenously or subcutaneously. SR-717 is a non-nucleotide, small-molecule STING agonist. small molecule sting agonist