Targeting sting with covalent small molecule inhibitors nature. Reference: Haag SM, et al.

Targeting sting with covalent small molecule inhibitors nature , … Ablasser, A. Targeting STING with covalent small-molecule inhibitors. Mechanistically, the identified compounds covalently target the predicted transmembrane cysteine Mar 6, 2019 · Haag, S. M. }, author={Hekang Du and Meng Kou and Weili Deng and Xueyuan Zhou and Xiaoxiong Zhang and The discovery of small molecule STING inhibitors, HSD1077 and analogs, which are facilely synthesized via a Povarov-Doebner type three-component reaction involving an amine, ketone, and aldehyde have the potential to be translated into anti-inflammatory compounds via STING inhibition. 1038/s41586-018-0287-8 PubMed Abstract | CrossRef Full Text | Google Scholar H-151 was discovered as a potent and selective STING antagonist that binds to STING Cys91, thereby inhibiting its palmitoylation and downstream activation. Cysteine-Directed Covalent Drugs. . STING Antagonist (C-178) is a potent inhibitor of the signaling molecule STING in mouse cells. ejmech. 164 To leverage the intrinsic symmetric nature of STING, the team focused on identifying small molecules that can bind to the STING homodimer in a 2:1 ratio while maintaining physicochemical properties suitable for Jul 20, 2023 · DOI: 10. Details. Metrics. Thielke and Luc{\'i}a Targeting STING with covalent small-molecule inhibitors. Nature 559 Jun 15, 2021 · Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. Here the authors design covalent inhibitors that target the papain-like protease from SARS-CoV-2. 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. H-151 is a potent antagonist of the signaling molecule STING in mouse and human cells. N. However, despite the tremendous clinical success of current covalent inhibitors, there are still unmet medical A small molecule, C53, binds the STING channel interface to block proton efflux and inhibit these responses, leaving STING phosphorylation and the TBK1-IRF3-Type I IFN axis active. Nature 559 , 269–273 (2018). Article CAS PubMed Google Scholar Thus, there is an urgent need to develop specific small-molecule STING antagonists. Aberrant activation of innate immune pathways is associated with a variety of diseases. Type Furthermore, we show that these small-molecule antagonists attenuate pathological features of autoinflammatory disease in mice. Apr 1, 2024 · Stimulator of interferon genes (STING) is a crucial endoplasmic reticulum membrane receptor involved in innate immunity. Ishikawa H. 1,2 It binds to STING, inhibits its palmitoylation, and prevents the recruitment and phosphorylation of TBK1. 2018 Jul;559(7713):269-273. Jul 15, 2021 · Merck scientists have reported the discovery of orally available STING antagonists that bind to the STING competitive binding site. B. Liu J, Yuan L, Ruan Y, et al. Dec 1, 2020 · Mechanism of small molecule inhibitors targeting STING. [Google Scholar] 29. Epub 2018 Jul 4 PubMed. We assessed structural and functional cardiac remodeling, infarct expansion and fibrosis, as well as cardiomyocyte hypertrophy and the expression of Jul 4, 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 component of the intracellular DNA sensing pathway 1,2. HEK mC-STING, HEK293T cells expressing mCherry–STING. 1021/acsptsci. Jul 4, 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 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 The identified compounds and their derivatives reduce STING-mediated inflammatory cytokine production in both human and mouse cells. 2022. Dec 1, 2020 · ADU-S100 and another CDN analogue MK-1454 are now in a number of clinical trials. 2019; 567:262-266. Article CAS PubMed Google Scholar Feb 29, 2024 · Covalent small-molecule modification of STING cysteines has been proposed to abrogate both palmitoylation and signalling 175, although these findings remain preliminary owing to the use of Dec 31, 2023 · Preclinical Evaluation of 131I/18F‑Labeled Covalent Small-Molecule Inhibitors for STING Status Imaging Jianyang Fang,⊥ Xiaobo Wang,⊥ Lingxin Meng, Jingru Zhang, Rongqiang Zhuang, Yesen Li, Furthermore, we show that these small-molecule antagonists attenuate pathological features of autoinflammatory disease in mice. Article ADS CAS Google Scholar Nov 4, 2022 · Recently, small-molecule covalent inhibitors have been accepted as a practical tool for targeting previously “undruggable” proteins. Oct 1, 2023 · H151 is a newly-discovered covalent inhibitor of STING. such as C-170, H151, and SN011 (Fig. Nature 455:674-8. 1038/s41467-024-48922-w Corpus ID: 270120499; Small molecule induced STING degradation facilitated by the HECT ligase HERC4 @article{Mutlu2024SmallMI, title={Small molecule induced STING degradation facilitated by the HECT ligase HERC4}, author={Merve Mutlu and Isabel Schmidt and Andrew I Morrison and Benedikt Goretzki and Felix Freuler and Damien Begue and Oliver Simic and Nicolas May 28, 2024 · Recent advancements in psoriasis treatment have been remarkable, with the development of biologics and small-molecule inhibitors that offer enhanced efficacy and reduced side effects . However, aberrant cytosolic self-DNA in Aicardi-Goutière's syndr … Feb 1, 2023 · DOI: 10. May 31, 2021 · In addition to selective and non-selective small-molecule c-Met inhibitors, monoclonal antibodies against HGF ligand and c-Met are also effective strategies targeting the HGF/c-Met axis. Targeting STING oligomerization with small-molecule inhibitors. Oct 5, 2023 · Nature. ) Jul 6, 2018 · Targeting STING with covalent small-molecule inhibitors. Significance STING is an essential adaptor protein required for the inflammatory response to cytosolic DNA. Despite Jan 4, 2021 · Haag, S. , Boston Children’s Hospital. Type C-176 is a covalent inhibitor of stimulator of interferon genes (STING). 3c00398 Corpus ID: 269655367; Preclinical Evaluation of 131I/18F-Labeled Covalent Small-Molecule Inhibitors for STING Status Imaging. , 2018. J Med Chem. C-170 efficiently inhibits both mouse STING (mmSTING) and human STING (hsSTING). Nature. Nature, 559(7713), Targeting STING with covalent small-molecule inhibitors. , Gulen, M. 10 However, H151’s efficacy in sepsis remains unknown. In addition to covalent inhibitors, linkages that differ from 2 ′ 3 ′-cGAMPs in chemical nature. Webinars; NATURE MEDICINE ALK is a therapeutic target for lethal sepsis Dec 11, 2024 · The development of a first-in-class non-covalent small-molecule inhibitor of SARS-CoV-2 replication that targets the viral guanine-N7 methyltransferase NSP14 is reported. Dec 1, 2023 · Peptide-based covalent probes can target shallow protein surfaces not typically addressable using small molecules, yet there is a need for versatile approaches to convert native peptide sequences H-151 is an inhibitor of stimulator of interferon genes (STING). C-170 is an inhibitor of stimulator of interferon genes (STING). @article{Liu2020DevelopmentOS, title={Development of small molecule inhibitors/agonists targeting STING for disease. W. @article{Zang2023DesignAS, title={Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist. Aug 14, 2018 · Stimulator of interferon genes (STING), an important component of the cytosolic DNA sensing pathway, is an attractive therapeutic target for ameliorating interferon-driven systemic Jul 1, 2018 · A chemical screen identifies small-molecule inhibitors of STING a, Screening workflow. C-170 exhibits binding affinity to the cysteine at the position Cys91 in both human and murine STING, effectively inhibiting the activation of the STING signaling pathway Oct 1, 2022 · In addition to the classical types of type I and II inhibitors that bind at the ATP-binding pocket, growing numbers of inhibitors have been reported as allosteric type III and IV inhibitors [13], covalent inhibitors [14], and bivalent inhibitors [15, 16], together with new chemical modalities, including molecular glues, proteolysis targeting Dec 2, 2019 · In addition, in this review, we summarize the STING inhibitors’ advances from two aspects, covalent, and noncovalent inhibitors. 113113 Corpus ID: 229693918; STING, a promising target for small molecular immune modulator: A review. 110945 Corpus ID: 227242610; Development of small molecule inhibitors/agonists targeting STING for disease. Date: 2018 Targeting STING with covalent small-molecule inhibitors. biopha. Progress in understanding the molecular mechanisms of innate immune pathways has led to the promise of targeted therapeutic approaches, but the development of drugs that act specifically on molecules of Mar 18, 2024 · Targeted covalent inhibitors (TCIs) can react irreversibly with lysine in kinases and other proteins. 1 It selectively reduces human and mouse STING-, but not RIG-I- or TBK1-, mediated IFN-β reporter activity in HEK293 cells when used at concentrations ranging from 0. This compound, BB-Cl-amidine inhibits STING signaling and production of type I IFNs, IFN-stimulated genes (ISGs) and NFκB-dependent cytokines, but not other pattern recognition receptors. Targeting STING with covalent small-molecule inhibitors The discovery and characterization of small-molecule antagonists that inhibit the stimulator of interferon genes protein may help develop therapies for the treatment of autoinflammatory disease. 2018;559:269–73. cGAS is an intracellular pattern recognition receptor (PRR) that detects double strand DNA and catalyzes the synthesis of the second The study explores small-molecule inhibitors targeting STING oligomerization and their impact on inflammatory responses. Aug 7, 2023 · There is an urgent need to develop specific small-molecule STING antagonists to advance the understanding of STING biology and create a paradigm in how to think about strategies for antagonizing STING function. May 9, 2024 · In this study, we develop novel inhibitor-based radioligands and evaluate their feasibility for noninvasive visualization of STING expression in tumor-bearing mice. H151 was intraperitoneally administrated for 8 consecutive days, commencing 1 h after photothrombotic stroke. The most Targeting STING with covalent small-molecule inhibitors Targeting STING with covalent small-molecule inhibitors. 1038/S41586-018-0287-8) Aberrant activation of innate immune pathways is associated with a variety of diseases. May 1, 2024 · DOI: 10. doi: 10. }, author={Liang Xue and Ruixue Liu and Lican Zhang and Tingting Qiu and Lu Liu and Ruijuan Yin and Oct 20, 2024 · The innate immune system plays a crucial role in detecting and responding to pathogenic infections. 4, 5 STING then induces phosphorylation of interferon regulatory factor-3 and NF-κB by Jul 1, 2018 · The discovery and characterization of small-molecule antagonists that inhibit the stimulator of interferon genes (STING) protein may help to develop therapies for the treatment of autoinflammatory disease. 2023. REFERENCES 1 Shekarian T , Valsesia-Wittmann S , Brody J , et al. It covalently binds to Cys91 of STING preventing activation via blockade of palmitoylation at Cys91. Dec 5, 2024 · In recent years, the intensified research on small-molecule STING inhibitors has led to the discovery of several molecules [12, 13]. It reduces systemic cytokine response in mice treated with the STING agonist 10-carboxymethyl-9-acridanone and showed efficacy in Trex-/- mice. A genome-wide CRISPR-Cas9 screen Aug 15, 2023 · Here, we identify and characterize a potent small-molecule inhibitor of STING. Novel CRBN-recruiting proteolysis-targeting chimeras as degraders of stimulator of interferon genes with in vivo anti-inflammatory efficacy. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I Target Diversified Drug Like Small Molecule Library; Target Focused Small Drug Like Molecule Library STING with covalent small-molecule inhibitors. In this study, we develop novel inhibitor-based radioligands and evaluate their feasibility for noninvasive visualization of STING expression in tumor-bearing mice. Here we report the discovery and Explore millions of resources from scholarly journals, books, newspapers, videos and more, on the ProQuest Platform. A. 2. F. 1038/s41586-018-0287-8 PMID: 29973723 Contributors Small-molecule inhibitors of STING oligomerization will advance our understanding of STING biology and create a paradigm in how we think about strategies for antagonizing STING function. , Reymond, L. 346691-38-1 C-170 is a potent and covalent inhibitor of STING. 32 H-151 can be used as both a human and a mouse STING inhibitor, and expression of type I interferon- and NF-κB–regulated genes was suppressed by H-151. Herein, we highlight the latest progress of small-molecule covalent PPIs inhibitors and hope to shed light on future PPIs inhibitor design and development. Haag S. Dec 19, 2024 · In the future, these covalent libraries could be used to identify covalent cyclic peptide inhibitors of a range of related therapeutically relevant enzymes, including bacterial arginine deiminases Dec 1, 2020 · The above-mentioned novel small molecule STING inhibitors have great potential in improving the treatment of human cancer, enriching the chemical space for the development of STING inhibitors, and providing more choices for the development of inhibitors. @article{Liu2020STINGAP, title={STING, a promising target for small molecular immune modulator: A review. edu (K. redox. The high target selectivity of modern covalent inhibitors is now alleviating toxicity concerns regarding the covalent modifications of proteins. By reviewing both Food and Drug Administration (FDA)-approved drugs and drug candidates from recent literature, we provide insight into the future Dec 2, 2024 · Carozza, J. (2018). Article CAS PubMed ADS Google Scholar Jun 25, 2024 · The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. 115188 Corpus ID: 260071313; DWL-4-140: A allene small molecule targeting STING that alleviates lupus-like phenotype in Trex1-/- mice. 1016/j. S. May 9, 2024 · The stimulator of interferon genes (STING) is a vital protein to the immune surveillance of the tumor microenvironment. specific small-molecule STING antagonists. }, author={Kaifeng Liu and Yongqi Lan and Xiaoling Li and Mingyue Li and Liao Cui and Hui Luo and Lianxiang Luo}, journal={Biomedicine Mar 28, 2023 · The development of direct-acting antivirals to combat COVID-19 remains an important goal. Nature, 559(7713), Feb 15, 2022 · We investigated novel and selective small-molecule STING inhibitors that inhibit STING palmitoylation and multimerization and thereby downstream pathway activation in a preclinical murine MI model. Small molecule inhibitors targeting STING have demonstrated therapeutic efficacy against these conditions. Nature 2018-07-04 | Journal article DOI: 10. 15 We previously showed that H151 effectively reduces injury, inflammation, and mortality after intestinal ischemia-reperfusion. M. The activation of STING is a multi-step process that includes binding with cGAMP, self-oligomerization, and translocation from the endoplasmic reticulum to the Golgi apparatus, ultimately inducing the expression of IRF3 and NF-κB-mediated interferons and Read our review: Follow the path to STING References: 1. & Barber G. Cell Chem Biol 27, 1347–1358 e1345 (DOI: 10. 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 inhibitors/agonists that targeted STING for cancer, autoimmune, and inflammatory diseases. Analogous compounds to STING inhibitors C170 and C176 were synthesized and labeled with 131I and 18F to attain May 29, 2024 · DOI: 10. One of the key components of this system is the cyclic GMP-AMP synthase (cGAS)-STING pathway, which serves as a defense barrier against invading pathogens. A STING inhibitor could be used as a pharmaceutical “kill switch” in the event that systemic STING agonist administration triggers adverse immune events in a patient. dsDNA activates cGAS to generate cGAMP, which binds and activates STING triggering a conformational change, oligomerization, and the IRF3- and NFκB-dependent transcription of type I Interferons (IFNs) and inflammatory cytokines, as well as the activation of autophagy. @article{Zhao2022SmallMT, title={Small molecules targeting cGAS-STING pathway for autoimmune disease. We found a significant Apr 4, 2021 · Introduction. ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors—A STING in the Tale of ENPP1 Kenneth I Onyedibe 1 Chemistry Department, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA; konyedib@purdue. Nov 21, 2024 · To facilitate their characterization, we propose a new classification for small-molecule BET BrD inhibitors based on target selectivity: type I for pan-BET BrD inhibitors, which are non-selective scientific article published in Nature. 01 to 5 μM. The potency and selectivity of small-molecule drugs can be improved via introducing cysteine-targeting elements that can covalently bind to their targets [13,19]. The radiosynthesis was May 22, 2023 · After screening more than 1,700,000 compounds from the Chinese National Compound Library, 8 we identified 1851 hits targeting 3CL pro. Ritchie C, Carozza JA, Li L, Biochemistry Cell Biology, and pathophysiology of the Innate Immune cGAS-cGAMP-STING pathway. Loading Loading research article Apr 18, 2023 · Activity-based protein profiling using small-molecule probes allows for direct identification of active enzymes, probing of target engagement by small-molecule inhibitors, and characterization of Aug 1, 2022 · The binding of mis-localized dsDNA initiates cGAS activation to synthesize a noncanonical cGAMP, which diffuses and mobilizes STING for innate immune responses [23]. 1 The sources of DNA that induce cyclic dinucleotides (CDNs) include the genomes of invading pathogens, including herpes simplex virus 1 (HSV-1) and cytomegalovirus, whereas certain bacteria can secrete CDNs (eg, Listeria specific small-molecule STING antagonists. Small-molecule inhibitors of STING oligomerization will advance our understanding of STING biology and create a paradigm in how we think about strategies for antagonizing STING function. 1 It selectively reduces STING-, but not RIG-I or TBK1-, mediated IFN-β reporter activity in HEK293 cells when used at concentrations ranging from 0. 2018 . By silico screening of drug libraries, several antagonists of cGAS have been developed from antimalarial drugs (AMDs), including hydroxychloroquine (HCQ), quinacrine (QC), and ACMA, to target the deleterious effects of cGAS-STING DOI: 10. Taken together with molecular docking and cell-based antiviral Apr 8, 2024 · H151 is a highly potent and selective small-molecule covalent antagonist of STING . }, author={Ruochen Zang and Liang Xue and Meifang Zhang and Xiaoyu Peng and Xionghao Li and Kaixin Du and Chuanqin Shi and Sep 26, 2019 · To sum up, the innovative study revealed the inhibitory mechanism of STING on pharmacology and showed the potential of STING inhibitors in the treatment of autoinflammatory diseases. Furthermore, we show that these small-molecule antagonists attenuate pathological features of autoinflammatory disease in mice. Jul 4, 2018 · Targeting STING with covalent small-molecule inhibitors. , Gibelin, A. Feb 4, 2019 · Nature Chemical Biology - Using biochemical and NMR studies, a class of small-molecule inhibitors termed BAX activation inhibitors were found to bind directly to a previously unrecognized pocket of Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, et al. Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP. Targeting STING with covalent small-molecule inhibitors (Q59059814) From Wikidata. 2018;559(7713):269–73. Nature 559, 269–273. Jun 21, 2021 · However, successful epigenetic drug discovery is still facing challenges, including moderate selectivity, limited efficacy, and acquired drug resistance. Overview of attention for article published in Nature, July 2018 STING with covalent small-molecule Aug 7, 2023 · Request PDF | Targeting STING oligomerization with small-molecule inhibitors | Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to Targeting STING with covalent small-molecule inhibitors. It also reduces increases in mouse serum levels of IFN Jul 28, 2023 · DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Progr erstandin lecular Jul 4, 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 component of the intracellular DNA sensing pathway 1,2. Reference: Haag SM, et al. Gulen , Luc reymond 2, Antoine Gibelin , Laurence Abrami 1, Alexiane Decout , Michael Heymann 1, F. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. 1 It forms an adduct with mouse STING in serum and acts in an irreversible manner. MW 322. STING is activated by 2′-3′-cyclic GMP-AMP, which is produced when cyclic GMP-AMP synthase (cGAS) senses foreign DNA. Nov 10, 2023 · Early enthusiasm for this target stemmed from a 2018 Nature paper about a covalent small molecule called H-151 that inhibited STING by modifying a cysteine, and thereby blocking post-translational May 21, 2019 · The authors present small-molecule inhibitors of human cGAS, characterize their interaction with the protein, and show that the compounds are active in interferon-producing cells including primary human macrophages. 1). Jul 6, 2018 · Targeting STING with covalent small-molecule inhibitors. Explore millions of resources from scholarly journals, books, newspapers, videos and more, on the ProQuest Platform. Small molecule STING agonists have also been pursued and GSK-3745417, one of the dimeric ABZIs, is the first small molecule suitable for systemic administration and has recently been investigated in human clinical study. PMID: 35452223. Read more related scholarly scientific articles and abstracts. 3. Targeting STING with covalent small-molecule inhibitors Aberrant activation of innate immune pathways is associated with a variety of diseases. CYCLIC GMP-AMP SYNTHASE (cGAS) is the sensor protein Aug 22, 2024 · The development of STING inhibitors for the treatment of STING-related inflammatory diseases continues to encounter significant challenges. It inhibits the type I interferon (IFN) response and reduces the phosphorylation of TBK1 and palmitoylation of human STING (hsSTING) in vitro. Reviewers: D. Jump to navigation Jump to search. 103202 Corpus ID: 269969457; Development of nitroalkene-based inhibitors to target STING-dependent inflammation @article{Chang2024DevelopmentON, title={Development of nitroalkene-based inhibitors to target STING-dependent inflammation}, author={Fei Chang and Camilla Gunderstofte and Nicole Colussi and Mareena Pitts and Sonia Salvatore and Anne L. LETTER OPEN Discovery of novel non-peptidic and non-covalent small-molecule 3CLpro inhibitors as potential candidate for COVID-19 treatment Signal Transduction and Targeted Therapy (2023) 8:209 Jul 19, 2021 · Haag, S. Targeting STING with covalent small-molecule inhibitors Targeting STING with covalent small-molecule inhibitors. Aug 5, 2022 · However, the small molecule inhibitors of the cGAS-STING pathway are still in the early stage, and the currently reported inhibitors only showed limited potency with poor druglike properties. 2020. O. Recommends. Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in Feb 8, 2021 · Targeting STING with covalent small-molecule inhibitors. b, Left, summary of the primary screen. Progress in understanding the molecular mechanisms of innate immune pathways has led to the promise of Feb 22, 2019 · A full decade has passed since STING was first described as an important innate signaling molecule. Created with Oct 4, 2024 · While covalent targeting has long played a subordinate role in drug developments, there has been a recent surge of interest in the application of the so-called targeted covalent inhibitors (TCIs Nov 1, 2023 · Compound C, a small-molecule AMPK inhibitor, also inhibits the DNA-dependent cGAS-STING pathway by reducing cGAMP accumulation, potentially modulating the cGAS-STING-mediated DNA-sensing pathway. et al. 2018 Jul;559(7713 Areas covered Small-molecule STING inhibitors reported in patents (disclosed before May 2022 through the public database at https://worldwide. Inspired by the advantages of covalent small-molecule inhibitors, targeted covalent inhibition has attracted increasing interest in epigenetic drug discovery. 27 Da, Purity >=98%. H151 inhibits the STING pathway by preventing its multimerization at the Golgi apparatus, which is required for downstream signaling. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. 114480 Corpus ID: 248950305; Small molecules targeting cGAS-STING pathway for autoimmune disease. }, author={Jiannan Zhao and Ruoxuan Xiao and Ruoqing Zeng and Ende He and Ao Zhang}, journal={European journal of medicinal chemistry}, year={2022}, volume={238}, pages Haag, S. The general structure of the electrophilic library sorted by warhead chemistries. by Simone M Haag, Muhammet F Gulen, Luc Reymond, Antoine Gibelin, Laurence Abrami, Alexiane Decout, Michael Heymann, F Gisou van der Goot, Gerardo Turcatti, Rayk Behrendt, Andrea Ablasser. , University of Washington; and I. May 1, 2022 · DOI: 10. Small molecule TCIs can have both broad or specific lysine targeting whereas peptide- and May 21, 2019 · Haag, S. The activation of the cyclic GMP-AMP synthase-stimulator of interferon gene (STING) pathway has been associated with the The discovery of a mechanism to pharmacologically inhibit STING should lead to new treatments for such diseases. 1,50,51 STING was identified as a strong inducer of type I IFNs through the activation of TANK May 5, 2020 · The cGAS-STING pathway is a major mechanism that mammalian cells utilize to detect cytoplasmic dsDNA from incoming viruses, bacteria, or self. Please login to recommend the paper. 1, 2, 3 This activation causes STING to move to Golgi apparatus. Haag S, Gulen M, Reymond L, et al. Jun 21, 2021 · Fragment screening and medicinal chemistry optimization led to development of a small-molecule inhibitor of RING1B–BMI1 E3 ligase, blocking the H2A ubiquitination activity of the Polycomb Nov 14, 2024 · Small molecule, active-site inhibitors binding to apo-IDO1 10,11, holo-IDO1 12,13,14 and holo-TDO2 15 have been reported, as well as dual inhibitors of holo-IDO1 and holo-TDO2 16,17,18. 7 days after injury, increased levels of phosphorylated TBK1 was observed, which indicated STING signaling activation [ 35 ]. Article ADS CAS Google Scholar Haag, S. }, author={Yijun Liu and Xin Lu and Nan Qin and Yuting Qiao and Shuaishuai Xing and Wenyuan Liu and Feng Feng and Zongliang Liu and Haopeng Sun}, journal Apr 22, 2022 · A series of STING protein degraders based on a small-molecule STING inhibitor and pomalidomide demonstrated moderate STING-degrading activities, and SP23 represents the first PROTAC degrader of STing deserving further investigation as a new anti-inflammatory agent. The discovery of a mechanism to pharmacologically inhibit STING should lead to new treatments for such diseases. , Abrami, L. com) were summarized in this review and the available structure–activity relationships (SARs) and molecular mechanisms of action were presented. Moreover, employing degradants to target STING represents a novel approach to drug des … Apr 7, 2022 · The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. For electrospray ionization spectra, see Supplementary Information. dsDNA activates cGAS to generate cGAMP, which binds and activates STING Dec 5, 2024 · Aberrant activation of the innate immune molecule STING can initiate inflammation and autoimmune diseases. ); wang3684@purdue. Article ADS CAS Google Scholar Nov 1, 2020 · DOI: 10. Pattern recognition receptors: immune targets to enhance cancer immunotherapy . Based on May 9, 2024 · DOI: 10. Mechanistically, the identified compounds covalently target the predicted transmembrane cysteine Targeting STING with covalent small-molecule inhibitors Simone M. Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to cytosolic DNA. 2024. 2008. M24296 CAS No. 116883 Corpus ID: 272678401; Discovery of novel nitrofuran PROTAC-like compounds as dual inhibitors and degraders targeting STING. Keywords: stimulator of interferon genes, protein arginine deiminases, cytokines, small-molecule inhibitor, Trex-1 Nov 23, 2024 · The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising Apr 8, 2021 · Insights into the structural and molecular biology of the cGAS–STING pathway have enabled the development of selective small-molecule inhibitors with the potential to target the cGAS–STING On the other hand, covalent inhibitors that target non-conserved protein residues demonstrate improved selectivity over related protein family members. Analogous compounds to STING inhibitors C170 and C176 were synthesized and labeled with 131 I and 18 F to attain [131 I]I-NFIP and [18 F]F-NFEP, respectively. Reference: 1. Progress in understanding the molecular mechanisms of innate immune pathways has led to the promise of targeted therapeutic approaches, but the development of drugs that act specifically on molecules of interest remains challenging. May 29, 2024 · In this work, we describe the characterization of the small molecule AK59-51TB (in short AK59) that inhibits the cGAS/STING pathway via degradation of STING. @article{Xue2024DiscoveryON, title={Discovery of novel nitrofuran PROTAC-like compounds as dual inhibitors and degraders targeting STING. Another class of small covalent inhibitors (C-176), with a different structure from H-151, shows a preferential effect at mouse STING The compound H-151 binds to the stalk region of STING, preventing the dimerization (multimerization) required for the activation of STING. Much more studies and more cautions on safety are urgently needed, since patients with autoimmune diseases clinically need long-term medication and Dec 18, 2020 · DOI: 10. Aug 18, 2023 · Targeting STING with covalent small-molecule inhibitors. Haag 1,4, Muhammet F. }, author={Jianyang Fang and Xiaobo Wang and Lingxin Meng and Jing-Ren Zhang and Rongqiang Zhuang Jan 4, 2021 · Haag, S. Dec 2, 2019 · In addition, in this review, we summarize the STING inhibitors’ advances from two aspects, covalent, and noncovalent inhibitors. 02 to 2 µM. @article{Fang2024PreclinicalEO, title={Preclinical Evaluation of 131I/18F-Labeled Covalent Small-Molecule Inhibitors for STING Status Imaging. I. Gisou van der Goot , Gerardo t urcatti 2, rayk Behrendt 3 & Andrea Ablasser 1* Aberrant ctivation nate mmun athway sociated ith riet eas. 1038/s41586-018-0287-8. @article{Du2023DWL4140AA, title={DWL-4-140: A allene small molecule targeting STING that alleviates lupus-like phenotype in Trex1-/- mice. 44 Additionally, Nrf2 has been shown to negatively regulate STING expression by decreasing STING mRNA stability. Jan 1, 2019 · To address this concern, covalent STING inhibitors have recently been identified that can reduce inflammatory cytokines induced by STING agonists . espacenet. 2022 May 12;65(9):6593-6611. Stimulator of interferon genes (STING) is an endoplasmic reticulum protein that acts as an indirect sensor of cytoplasmic double-stranded DNA (dsDNA). Nature 559:269-73. This review categorized representative covalent inhibitors based on their mechanism of covalent inhibition: conventional covalent inhibitors, targeted covalent inhibitors (TCIs), and expanded TCIs. edu (M. 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 pathway1,2. 115184 Corpus ID: 256612252; Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist. 2. Z. Dec 14, 2021 · Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, et al. , Decout, A. from publication: Targeting STING with covalent small-molecule inhibitors | Aberrant activation of innate immune pathways is C-170( STING-IN-2 ) Catalog No. kvjs trb jsvn rsmdyjp fiavci asnw msrkom rqij yplg jevyeu