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Review Article

Inhibitors of Stimulator of Interferon Genes from 2019 to July 2022: An Overview of the Structure and Bioactivity

Author(s): Feng Xu, Xinjian Tian, Qiangsheng Zhu, Ziwen Feng, Hui Li, Wei Dai, Yeling Zhou, Qi-Dong You* and Xiaoli Xu*

Volume 24, Issue 12, 2023

Published on: 12 September, 2023

Page: [959 - 980] Pages: 22

DOI: 10.2174/1389450124666230831160820

Price: $65

Abstract

Stimulator of interferon genes (STING) plays a vital role in the human innate immune system. Aberrant expression of STING has been proven to be associated with several diseases, such as STING-associated vasculopathy with onset in infancy, Aicardi-Goutieres syndrome, and systemic lupus erythematosus. Therefore, inhibition of the STING signaling pathway can also be expected to provide effective therapeutic strategies for treating specific inflammatory and autoimmune diseases. However, the development of STING inhibitors is still in its infancy. There is still a need for additional efforts toward the discovery of new skeletons and more potent lead compounds for STING inhibition to meet clinical demand. In this review, we provide a summary of STING inhibitors, classified by different structural skeletons, reported in patents published from 2019 to July 2022. In addition, we also focus on the STING inhibitors, representative structures, biological activity, and mechanisms of action.

Keywords: STING, inflammatory and autoimmune diseases, inhibitors, representative structures, biological activity, interferon genes.

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[1]
Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140(6): 805-20.
[http://dx.doi.org/10.1016/j.cell.2010.01.022] [PMID: 20303872]
[2]
Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int Rev Immunol 2011; 30(1): 16-34.
[http://dx.doi.org/10.3109/08830185.2010.529976] [PMID: 21235323]
[3]
Bürckstümmer T, Baumann C, Blüml S, et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol 2009; 10(3): 266-72.
[http://dx.doi.org/10.1038/ni.1702] [PMID: 19158679]
[4]
Takaoka A, Wang Z, Choi MK, et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 2007; 448(7152): 501-5.
[http://dx.doi.org/10.1038/nature06013] [PMID: 17618271]
[5]
Unterholzner L, Keating SE, Baran M, et al. IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol 2010; 11(11): 997-1004.
[http://dx.doi.org/10.1038/ni.1932] [PMID: 20890285]
[6]
Yi G, Brendel VP, Shu C, Li P, Palanathan S, Cheng Kao C. Single nucleotide polymorphisms of human STING can affect innate immune response to cyclic dinucleotides. PLoS One 2013; 8(10): e77846.
[http://dx.doi.org/10.1371/journal.pone.0077846] [PMID: 24204993]
[7]
Ablasser A, Goldeck M, Cavlar T, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 2013; 498(7454): 380-4.
[http://dx.doi.org/10.1038/nature12306] [PMID: 23722158]
[8]
Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 2013; 339(6121): 786-91.
[http://dx.doi.org/10.1126/science.1232458] [PMID: 23258413]
[9]
Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 2008; 455(7213): 674-8.
[http://dx.doi.org/10.1038/nature07317] [PMID: 18724357]
[10]
An J, Durcan L, Karr RM, et al. Expression of cyclic GMP-AMP synthase in patients with systemic lupus erythematosus. Arthritis Rheumatol 2017; 69(4): 800-7.
[http://dx.doi.org/10.1002/art.40002] [PMID: 27863149]
[11]
Wang J, Li R, Lin H, et al. Accumulation of cytosolic dsDNA contributes to fibroblast-like synoviocytes-mediated rheumatoid arthritis synovial inflammation. Int Immunopharmacol 2019; 76: 105791.
[http://dx.doi.org/10.1016/j.intimp.2019.105791] [PMID: 31472320]
[12]
Woodward JJ, Iavarone AT, Portnoy DA. c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science 2010; 328(5986): 1703-5.
[http://dx.doi.org/10.1126/science.1189801] [PMID: 20508090]
[13]
Dey B, Dey RJ, Cheung LS, et al. A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis. Nat Med 2015; 21(4): 401-6.
[http://dx.doi.org/10.1038/nm.3813] [PMID: 25730264]
[14]
Burdette DL, Monroe KM, Sotelo-Troha K, et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature 2011; 478(7370): 515-8.
[http://dx.doi.org/10.1038/nature10429] [PMID: 21947006]
[15]
Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol 2021; 21(9): 548-69.
[http://dx.doi.org/10.1038/s41577-021-00524-z] [PMID: 33833439]
[16]
Zhao B, Du F, Xu P, et al. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. Nature 2019; 569: 718-22.
[http://dx.doi.org/10.1038/s41586-019-1228-x]
[17]
Tsuchiya Y, Jounai N, Takeshita F, Ishii KJ, Mizuguchi K. Ligand-induced Ordering of the C-terminal Tail Primes STING for Phosphorylation by TBK1. EBioMedicine 2016; 9: 87-96.
[http://dx.doi.org/10.1016/j.ebiom.2016.05.039] [PMID: 27333035]
[18]
Fang R, Wang C, Jiang Q, et al. NEMO–IKKβ are essential for IRF3 and NF-κB activation in the cGAS–STING pathway. J Immunol 2017; 199(9): 3222-33.
[http://dx.doi.org/10.4049/jimmunol.1700699] [PMID: 28939760]
[19]
Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol 2011; 12(10): 959-65.
[http://dx.doi.org/10.1038/ni.2091] [PMID: 21892174]
[20]
Margolis SR, Wilson SC, Vance RE. Evolutionary Origins of cGAS-STING Signaling. Trends Immunol 2017; 38(10): 733-43.
[http://dx.doi.org/10.1016/j.it.2017.03.004] [PMID: 28416447]
[21]
Liu Y, Lu X, Qin N, et al. STING, a promising target for small molecular immune modulator: A review. Eur J Med Chem 2021; 211: 113113.
[http://dx.doi.org/10.1016/j.ejmech.2020.113113] [PMID: 33360799]
[22]
Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med 2014; 371(6): 507-18.
[http://dx.doi.org/10.1056/NEJMoa1312625] [PMID: 25029335]
[23]
Gao D, Li T, Li XD, et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc Natl Acad Sci 2015; 112(42): E5699-705.
[http://dx.doi.org/10.1073/pnas.1516465112] [PMID: 26371324]
[24]
Gray EE, Treuting PM, Woodward JJ, Stetson DB. Cutting Edge: cGAS Is required for lethal autoimmune disease in the trex1-deficient mouse model of aicardi–goutières syndrome. J Immunol 2015; 195(5): 1939-43.
[http://dx.doi.org/10.4049/jimmunol.1500969] [PMID: 26223655]
[25]
Pokatayev V, Hasin N, Chon H, et al. RNase H2 catalytic core Aicardi-Goutières syndrome–related mutant invokes cGAS–STING innate immune-sensing pathway in mice. J Exp Med 2016; 213(3): 329-36.
[http://dx.doi.org/10.1084/jem.20151464] [PMID: 26880576]
[26]
Rice GI, Forte GMA, Szynkiewicz M, et al. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: A case-control study. Lancet Neurol 2013; 12(12): 1159-69.
[http://dx.doi.org/10.1016/S1474-4422(13)70258-8] [PMID: 24183309]
[27]
Kato Y, Park J, Takamatsu H, et al. Apoptosis-derived membrane vesicles drive the cGAS–STING pathway and enhance type I IFN production in systemic lupus erythematosus. Ann Rheum Dis 2018; 77(10): 1507-15.
[http://dx.doi.org/10.1136/annrheumdis-2018-212988] [PMID: 29945921]
[28]
Thim-uam A, Prabakaran T, Tansakul M, et al. STING mediates lupus via the activation of conventional dendritic cell maturation and plasmacytoid dendritic cell differentiation. iScience 2020; 23(9): 101530.
[http://dx.doi.org/10.1016/j.isci.2020.101530] [PMID: 33083760]
[29]
König N, Fiehn C, Wolf C, et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis 2017; 76(2): 468-72.
[http://dx.doi.org/10.1136/annrheumdis-2016-209841] [PMID: 27566796]
[30]
Jeremiah N, Neven B, Gentili M, et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest 2014; 124(12): 5516-20.
[http://dx.doi.org/10.1172/JCI79100] [PMID: 25401470]
[31]
Domizio JD, Gulen MF, Saidoune F, et al. The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. Nature 2022; 603(7899): 145-51.
[http://dx.doi.org/10.1038/s41586-022-04421-w]
[32]
Siu T, Altman MD, Baltus GA, et al. Discovery of a novel cGAMP competitive ligand of the inactive form of STING. ACS Med Chem Lett 2019; 10(1): 92-7.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00466] [PMID: 30655953]
[33]
Li S, Hong Z, Wang Z, et al. The cyclopeptide astin C specifically inhibits the innate immune CDN sensor STING. Cell Rep 2018; 25(12): 3405-3421.e7.
[http://dx.doi.org/10.1016/j.celrep.2018.11.097] [PMID: 30566866]
[34]
Haag SM, Gulen MF, Reymond L, et al. Targeting STING with covalent small-molecule inhibitors. Nature 2018; 559(7713): 269-73.
[http://dx.doi.org/10.1038/s41586-018-0287-8] [PMID: 29973723]
[35]
Hong Z, Mei J, Li C, et al. STING inhibitors target the cyclic dinucleotide binding pocket. Proc Natl Acad Sci 2021; 118(24): e2105465118.
[http://dx.doi.org/10.1073/pnas.2105465118] [PMID: 34099558]
[36]
Hansen AL, Buchan GJ, Rühl M, et al. Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling. Proc Natl Acad Sci 2018; 115(33): E7768-75.
[http://dx.doi.org/10.1073/pnas.1806239115] [PMID: 30061387]
[37]
Vinogradova EV, Zhang X, Remillard D, et al. An activity-guided map of electrophile-cysteine interactions in primary human T cells. Cell 2020; 182(4): 1009-1026.e29.
[http://dx.doi.org/10.1016/j.cell.2020.07.001] [PMID: 32730809]
[38]
Gao J, Zheng M, Wu X, et al. CDK inhibitor Palbociclib targets STING to alleviate autoinflammation. EMBO Rep 2022; 23(6): e53932.
[http://dx.doi.org/10.15252/embr.202153932] [PMID: 35403787]
[39]
Roush WR, Seidel HM, Venkatraman S, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2021138419A1 2021.
[40]
Roush WR, Venkatraman S, Glick G, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2020010092A1 2020.
[41]
Seidel HM, Roush WR, Katz J, et al. Oxalamide compounds and compositions for treating conditions associated with STING activity Patent WO2021067791A1 2021.
[42]
Venkatraman S, Katz J, Roush WR, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2020243519A1 2020.
[43]
Seidel HM, Roush WR, Venkatraman S, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2020150417A2 2020.
[44]
Venkatraman S, Katz J, Roush WR, et al. N-hetaryl-squaramide compounds for treating conditions associated with STING activity. Patent WO2020236586A1, 2020.
[45]
Venkatraman S, Katz J, Roush WR, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2022150543A1 2022.
[46]
Heer JP, Hallside MS, Smalley AP, et al. Pharmaceutical 6,5 heterobicyclic ring derivatives. Patent WO2019158731A1, 2019.
[47]
Seidel HM, Roush WR, Venkatraman S, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2021138434A1 2021.
[48]
Venkatraman S, Katz J, Roush WR, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2022150560A1 2022.
[49]
Venkatraman S, Katz J, Roush WR, et al. Heterobicyclic compounds having an urea or analogue and their compositions for treating conditions associated with sting activity Patent WO2022150585A1 2022.
[50]
Seidel HM, Roush WR, Katz J, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2021067801A1 2021.
[51]
Venkatraman S, Katz J, Roush WR, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2022015977A1 2022.
[52]
Li H, Zhong W, Huang W, et al. STING antagonists and uses thereof Patent WO2022105930A1 2022.
[53]
Venkatraman S, Katz J, Roush WR, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2022015938A1 2022.
[54]
Venkatraman S, Katz J, Roush WR, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2022015957A1 2022.
[55]
Venkatraman S, Katz J, Roush WR, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2022015975A1 2022.
[56]
Venkatraman S, Katz J, Roush W, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2022015979A1 2022.
[57]
Venkatraman S, Katz J, Roush WR, et al. Compounds and compositions for treating conditions associated with STING activity Patent US20220024906A1 2022.
[58]
Katz J, Venkatraman S, Roush W, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2020252240A1 2020.
[59]
Venkatraman S, Katz J, Roush WR, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2022133098A2 2022.
[60]
Venkatraman S, Katz J, Roush WR, et al. Compounds and compositions for treating conditions associated with STING activity Patent US20220024919 A1 2022.
[61]
Seidel H, Roush W, Venkatraman S, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2020150439A1 2020.
[62]
Seidel HM, Roush WR, Katz J, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2021067805A1 2021.
[63]
Venkatraman S, Katz J, Roush WR, et al. Oxalamide compounds and compositions for treating conditions associated with sting activity Patent WO2022150549 2022.
[64]
Venkatraman S, Roush WR, Seidel HM, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2020106736A1 2020.
[65]
Seidel HM, Roush WR, Katz J, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2022133046A1 2022.
[66]
Ablasser A, Reymond L, Haag S, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2019122202A1 2019.
[67]
Iyer R, Padmanabhan S, Baskaran S, et al. Compounds, compositions, and methods for the treatment of disease Patent WO2020181050A1 2020.
[68]
Altman M, Childers M, Jewell J, et al. Oxo-tetrahydro-isoquinoline carboxylic acids as STING inhibitors Patent WO2019182886A1 2019.
[69]
Kiyoi T, Matsumoto H, Takamatsu S, et al. Novel benzimidazole derivative Patent WO2021193756A1 2021.
[70]
Sun H, Wang C, You YP, et al. Amide compound and medical application thereof as STING inhibitor Patent CN112409223A 2021.
[71]
Ishii K, Nishida H, Imura Y, et al. Novel xanthenone derivative Patent WO2021200824A1 2021.
[72]
Banerjee M, Basu S, Shrivastava RK, et al. Small molecule STING antagonists Patent WO2021161230A1 2021.
[73]
Roush WR, Seidel HM, Venkatraman S, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2020106741A1 2020.
[74]
Roush W, Venkatraman S, Glick G, et al. Compounds and compositions for treating conditions associated with STING activity Patent US20210236466A1 2021.
[75]
Roush WR, Venkatraman S, Glick G, et al. Compounds and compositions for treating conditions associated with STING activity Patent WO2020010155A1 2020.
[76]
Wheeler D, Meyerson M, et al. Compositions and methods for modulating innate immune signaling pathways Patent WO2021077018A1 2021.
[77]
Laguette N, Guerra J, Nawrot B, et al. STING inhibitors and their therapeutic uses Patent WO2021043992A1 2021.
[78]
Guida WC, Daniel KG, Brooks WH, et al. STING modulators, compositions, and methods of use Patent WO2021042024A1 2021.
[79]
Chen HS, Li XS, Chen JJ, et al. Medical application of active substance for knocking down or inhibiting STING Patent CN112704684A 2021.
[80]
Lairson LL, Chin E, Shenvi R. Butenolide antagonists of the cGAS/STING pathway. Patent WO2020118206A1, 2020.
[81]
Zhang A, Tang W, Shen A, et al. Substituted indole urea derivative, synthetic method and application thereo Patent CN113248491A 2021.
[82]
Song P, Yang W, Lou KF, et al. UNC13D inhibits STING signaling by attenuating its oligomerization on the endoplasmic reticulum. EMBO Rep 2022; 23(11): e55099.
[http://dx.doi.org/10.15252/embr.202255099] [PMID: 36125406]
[83]
Luo WW, Tong Z, Cao P, et al. Transcription-independent regulation of STING activation and innate immune responses by IRF8 in monocytes. Nat Commun 2022; 13(1): 4822.
[http://dx.doi.org/10.1038/s41467-022-32401-1] [PMID: 35973990]

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