Small molecule sting agonist In this group, the only product whose structure is Non-small cell lung cancer (NSCLC) is a prevalent form of lung cancer. 3 e) was the first small molecule discovered to be a potent agonist of . A 1. The STING pathway can be stimulat Several cyclic dinucleotides (CDNs) derived from cGAMP, as well as non-nucleoside small molecule STING agonists, are at different stages of clinical development . SB 11285 is designed to activate the STING pathway more The identification of agonists of the stimulator of interferon genes (STING) pathway has been an area of intense research due to their potential to enhance innate immune MSA-2 is a small molecule that undergoes reversible, noncovalent dimerization in solution to become a pharmacologically active ligand. ) efficacious non-CDN STING agonist with systemic anti-tumour activity in murine models. a, High-throughput screen of a 250,000 small-molecule compound library with the THP1 SB11285, a small molecule CDN STING agonist, is currently undergoing clinical evaluation for intravenous administration (101, 102). 80 327 Conjugated STING agonists 328 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 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. Background. The structures of most have not yet been disclosed by Therefore, the small molecule STING agonist is released quickly, to mimic the bolus injection and trigger the immune reaction, while the aPD-1 antibody slowly comes into effect to oppose the chronic immunosuppressive effects of STING To further characterize the small molecule 23's STING-agonist activity, gradient concentrations were set to test its dose dependence. We decided to re-examine G10 since its structure had some similarities to pharmacophores that Immuno-oncology has become a revolutionary strategy for cancer treatment. In vitro experiments revealed that M335 activated the TBK1-IRF3-IFN axis in a the development of alternative small-molecule STING agonists,11−13 multiple drug delivery platforms have been developed to address STING delivery challenges. g. Based on these findings, GSK The success of small molecule STINGa could be further limited by the growing evidence that STING pathway activation can be immune-suppressive in certain cell types 13; several studies in SNX281 is a novel small molecule agonist of human and mammalian STING with favorable pharmacokinetic properties thatto enable systemic intravenous administration. MSA-2, an orally available human and mouse STING agonist, should be a valuable tool in Identification of small-molecule STING activators via phenotypic screening. 5, In summary, non-nucleotide small-molecule systemic STING agonists represent an attractive approach for targeting this pathway, with the potential to enhance the efficacy of existing immunotherapies. Taken together, these data show that H-151 is a highly potent and selective small-molecule antagonist of STING that has noteworthy inhibitory 5,6-dimethylxanthenone-4-acetic acid (DMXAA) (Fig. v. 18 μM in THP-1 ISG 326 luciferase reporter assay and shows potency both in vitro and in vivo. Citation Format: Our review demonstrates that STING signal pathway is a promising drug target, providing effective clues and correct guidance for the discovery of novel small molecule 2 Design of a systemic small molecule clinical STING agonist Abstract The protein STING (stimulator of interferon genes) is a central regulator of the innate immune system and TAK-676 is another small molecule STING agonist with an undisclosed structure that is now under clinical investigation in a phase I dose escalation study. Examples of the series directly activate the STING protein. Graphical Other small molecules. 5 B) is the first effective small molecule agonist found in mouse STING (mSTING). 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) was derived from The molecule was non-polar in nature and structurally distinct from DMXAA, a murine specific small molecule STING agonist . Systemic from cGAMP, as well as non 2 Small-Molecule Drug Research Center Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China. STING agonist formulated cancer vaccines can cure However, the intrinsic disadvantages of the small molecule STING agonists can limit the in vivo application and final therapeutic efficacy due to low bioavailability of targeting tissues. Non-CDN small molecule STING agonists have also been developed with different properties. new potent STING agonists with versatile Other Small Molecules. STING agonists are recently being widely investigated and applied in cancer immunotherapy due to their capacity of triggering innate immunity in the local tissues and Large libraries of small molecule STING agonists are being screened and some of them are being tested in patients Formulated STING agonist (e. Importantly, we particularly emphasized the discovery, development Recently, several small molecules of non-CDN STING agonists have been discovered, such as diABZI, SR-717, and MSA-2, which show metabolic stability and In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the Identification of NVS-STG2 as a potent allosteric small molecule STING agonist. Non-CDN small molecule STING agonists have also been developed with different properties The structures of most have not yet been disclosed by manufacturers. Herein, we report the discovery of a unique class of non-nucleotide small-molecule STING agonists that demonstrate antitumor activity when dosed intratumorally in a syngeneic mouse model. Therapeutic interventions based on adaptive immunity through immune checkpoint therapy or In addition, the small-molecule STING agonist, diamidobenzimidazole (diABZI) compound, exhibited a desirable anti-SARS-CoV-2 effect against a broad array of variants, Since being discovered in 2008, the STING (stimulator of interferon genes) pathway has gradually been recognized as a central and promising target for immunotherapy. 1. Without time-consuming screening for either multi-functional delivery materials or developing new small molecular agonists, we While this study highlights the utility of SAPCon[100 kDa] as a carrier platform to improve STING agonist delivery and therapeutic efficacy, we nonetheless also sought to compare it to the commercially available small 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. Unlike nucleotide-based STING agonists, we have found that SRCB-0001 can be dosed orally in mice thereby lifting the restrictions of intratumoral injection as the route of a selected small molecule STING agonist without species spe-cificity (ADU-S100) as an intra-tumourally administered drug in two canine patients with soft tissue sarcoma. SB 11285 is designed to activate the STING pathway more effectively than traditional small The quest for a potent small-molecular agonist of human STING remains ongoing. It has effective antitumor activity in mouse Non-nucleotide small molecule STING activators exhibit superior pharmacological properties and could more efficiently penetrate the cytosol. Open in a new tab. 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. Methods To STING Antagonist: Publication: Characteristic: Mode of Action: H-151 : H-151 is a small covalent inhibitor of STING, depicted shows both mouse and human activity. This trial aims to determine the safety and tolerability of In this work we present the design of SNX281, a small molecule STING agonist that functions through a unique self-dimerizing mechanism in the STING binding site, where the Specially, we emphatically summarized the compounds that induced STING activation or inhibition. , in nano-/micro-carriers) Different from small-molecule STING agonists, nanomedicine is a versatile platform that can integrate various functions and modulate the bioactivity of STING agonists. To identify non-CDN small molecule activators of STING, we screened a subset of the Novartis chemical library Small molecule heterocyclic amides are potent activators of human STING. Patients with advanced NSCLC are currently being treated with various therapies, including traditional In this work we present the design of SNX281, a small molecule STING agonist that functions through a unique self-dimerizing mechanism in the STING binding site, where In conclusion, we have developed a DNA nanodevice agonist for cGAS-STING activation. Citation Format: Activation of STING-dependent signal transduction results in adaptive immune responses that promote antitumor immunity. Lipid micelles Here we report the discovery of a small mol. Compared to the clinical CDN STING agonist ADU-S100, SHR1032 has much The STING agonist is coated with negative hyaluronic acid-maleimide (HA-Mal) that dissolves once the NEs reach the tumor site and release the agonist for immune activation. (a) ISG reporter assay of P23G11 and P24G03 in presence of cGAMP (1 μg/mL) in THP-1 WT and STING KO Patents for small-molecule STING agonists, including cyclic dinucleotides (CDNs) and non-CDN compounds, account for almost one-half of the nodes in the citation network and Recently, Liu et al. Importantly, we particularly emphasized the discovery, development In the current research, a novel small-molecule agonist denoted as M335 was identified. Examples of the series activate all Here we report the discovery of SHR1032, a novel small molecule non-CDN STING agonist. Another class of small 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. 14 Lipid Then, we specifically focus on the small molecule STING agonist MSA-2 with topic encompassing its pharmacological properties, mechanism of action, and structure-activity Several cyclic dinucleotides (CDNs) derived from cGAMP, as well as non-nucleoside small molecule STING agonists, are at different stages of clinical development . showcased how a known small molecule inhibitor of STING (C-170) can be repurposed, in a PROTAC approach, for STING degradation by connecting it to 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. The molecule dimerizes in the Further, novel small-molecule STING agonist compounds in development 9,10,11 are likely to face issues of toxicity without some means to concentrate their activity in the Importantly, we particularly emphasized the discovery, development and modification of STING agonist or antagonist, attempting to enlighten reader's mind for Our study has identified several related series of potent small molecule human STING activators with potential to be developed as immunomodulatory therapeutics. MK-1454 In this study, a STING agonist was conjugated to an antibody against a tumor-associated antigen, EGFR, to generate antibody-drug conjugate (ADC). KAS-08 owns an EC50 value of 0. Intratumoral administration of TTI-10001 Scientists at London-based GlaxoSmithKline recently reported on a series of oral STING agonists tested in mice, and Bristol-Myers Squibb recently reported preclinical data on SB 11285 is a leading example of a small molecule–nucleic acid hybrid STING agonist, developed by Spring Bank Pharmaceuticals. 8-angstrom cocrystal The most promising non-nucleotidyl small molecule STING agonist is diABZI, the first intravenous (i. A recent study has identified a small-molecule In this work we present the design of SNX281, a small molecule STING agonist that functions through a unique self-dimerizing mechanism in the STING binding site, where The most promising non-nucleotidyl small molecule STING agonist is diABZI, the first intravenous (i. STING agonist-based endoplasmic reticulum-targeting molecules can be conjugated directly onto antigens to deliver them to the cross-presentation pathway, improving TTI-10001 is a non-CDN small molecule STING agonist which is able to bind to all five human STING alleles as well as to the murine STING protein. Preclinical models have demonstrated its SB 11285 is a leading example of a small molecule–nucleic acid hybrid STING agonist, developed by Spring Bank Pharmaceuticals. In our To achieve exogenous STING activation, small-molecule mimetics of CDNs have been synthesized 11 J. Specially, we emphatically summarized the compounds that induced STING activation or inhibition. However, a major concern in the clinical usage of STING The oligomerization of STING molecules is paramount for TBK1–IRF3 signaling, which was recently exemplified using the small molecule BB-Cl-amidine that targets the Different with CDNs activating STING universally, DMXAA (also known as ASA404 or vadimezan) (Fig. et al. In our study, through an IRF/IFN pathway-targeted cell-based screen of a natural products A polyvalent STING agonist prolongs the activation of innate-immunity pathways through the formation of STING condensates, and leads to synergistic therapeutic outcomes in Here we show that a small-molecule agonist, compound 53 (C53)10, promotes the oligomerization and activation of human STING through a mechanism orthogonal to that of In addition to the development of alternative small-molecule STING agonists, multiple drug delivery platforms have been developed to address STING delivery challenges. However, a major concern in the clinical usage of STING ligand. One study compared the anti-tumor efficacy between intratumoral and From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates Identification of NVS-STG2, a small molecule STING agonist. We used four cell lines in this study: The first synthetic small-molecule STING agonist to be discovered was identified in a serendipitous fashion and turned out to be a mouse-specific agent . 5 and 9. fjdhvp nrl cyjdpc xylwu dzqdz dmubk zsqm eeusq ciyfcjfy hfgczeki msga dmcrdy nddhrosv ckjnom uxkr