Skip to main content
Springer Nature Link
Log in

Discovery of isoindoline-2(1H)-carboxamide STING inhibitors as anti-inflammatory agents

  • Original Article
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

See More

STING (stimulator of interferon genes) is an endoplasmic reticulum-resident membrane-spanning protein that is widely expressed in mammalian cells and functions as a central regulator for the innate immunity. Aberrant activation of the STING axis due to loss-of-function or gain-of-function mutation leads to various autoimmune and autoinflammatory disorders such as Aicardi-Goutières syndrome, systemic lupus erythematosus, and STING-associated vasculopathy with onset in infancy. Here we report the design, synthesis, and structure–activity relationship (SAR) of the isoindoline-2(1H)-carboxamide STING inhibitors. SAR study allowed us to identify compound 3b as a potent STING inhibitor with human- and mouse-STING inhibitory IC50 values of 6.2 and 12.5 nM, respectively. It also markedly suppressed the activation of the STING pathway in both human and murine cells. Furthermore, compound 3b exhibited preferable in vivo protective efficacy against cisplatin-induced acute kidney injury.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Fig. 3
Fig. 4 
Fig. 5

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

Data availability

No datasets were generated or analysed during the current study.

References

  1. Liu J, Yuan L, Ruan Y, Deng B, Yang Z, Ren Y, Li L, Liu T, Zhao H, Mai R, Chen J (2022) Novel CRBN-recruiting proteolysis-targeting chimeras as degraders of stimulator of interferon genes with in vivo anti-inflammatory efficacy. J Med Chem 65:6593–6611

    Article  CAS  PubMed  Google Scholar 

  2. Liu J, Zhou J, Luan Y, Li X, Meng X, Liao W, Tang J, Wang Z (2024) cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation. Cell Commun Signal 22:22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ishikawa H, Barber GN (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455:674–678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yu L, Liu P (2021) Cytosolic DNA sensing by cGAS: regulation, function, and human diseases. Signal Transduct Target Ther 6:170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Civril F, Deimling T, de Oliveira Mann CC, Ablasser A, Moldt M, Witte G, Hornung V, Hopfner KP (2013) Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498:332–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang X, Shi H, Wu J, Zhang X, Sun L, Chen C, Chen ZJ (2013) Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol Cell 51:226–235

    Article  CAS  PubMed  Google Scholar 

  7. Yu X, Zhao Z, Jiang Z (2022) Recent progress on the activation of the cGAS-STING pathway and its regulation by biomolecular condensation. J Mol Cell Biol 14:mjac042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang C, Shang G, Gui X, Zhang X, Bai XC, Chen ZJ (2019) Structural basis of STING binding with and phosphorylation by TBK1. Nature 567:394–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Balka KR, Louis C, Saunders TL, Smith AM, Calleja DJ, D’Silva DB, Moghaddas F, Tailler M, Lawlor KE, Zhan Y, Burns CJ, Wicks IP, Miner JJ, Kile BT, Masters SL, De Nardo D (2020) TBK1 and IKKε act redundantly to mediate STING-induced NF-κB responses in myeloid cells. Cell Rep 31:107492

    Article  CAS  PubMed  Google Scholar 

  10. Dobbs N, Burnaevskiy N, Chen D, Gonugunta VK, Alto NM, Yan N (2015) STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host Microbe 18:157–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xie Z, Wang Z, Fan F, Zhou J, Hu Z, Wang Q, Wang X, Zeng Q, Zhang Y, Qiu J, Zhou X, Xu H, Bai H, Zhan Z, Ding J, Zhang H, Duan W, Yu X, Geng M (2022) Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation. Cell Discov 8:133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Skopelja-Gardner S, An J, Elkon KB (2022) Role of the cGAS-STING pathway in systemic and organ-specific diseases. Nat Rev Nephrol 18:558–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang Z, Zhou H, Ouyang X, Dong Y, Sarapultsev A, Luo S, Hu D (2022) Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy. Signal Transduct Target Ther 7:394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fazzi E, Cattalini M, Orcesi S, Tincani A, Andreoli L, Balottin U, De Simone M, Fredi M, Facchetti F, Galli J, Giliani S, Izzotti A, Meini A, Olivieri I, Plebani A (2013) Aicardi-Goutieres syndrome, a rare neurological disease in children: a new autoimmune disorder? Autoimmun Rev 12:506–509

    Article  CAS  PubMed  Google Scholar 

  15. Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, de Silva U, Bailey SL, Witte T, Vyse TJ, Kere J, Pfeiffer C, Harvey S, Wong A, Koskenmies S, Hummel O, Rohde K, Schmidt RE, Dominiczak AF, Gahr M, Hollis T, Perrino FW, Lieberman J, Hübner N (2007) Mutations in the gene encoding the 3’-5’ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 39:1065–1067

    Article  CAS  PubMed  Google Scholar 

  16. Pan Y, You Y, Sun L, Sui Q, Liu L, Yuan H, Chen C, Liu J, Wen X, Dai L, Sun H (2021) The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation. Br J Pharmacol 178:4907–4922

    Article  CAS  PubMed  Google Scholar 

  17. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GAM, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CR, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R (2014) Activated STING in a vascular and pulmonary syndrome. N Engl J Med 371:507–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RRJ, Moecking J, De Nardo D, Balka KR, Calleja DJ, Moghaddas F, Ni E, McLean CA, Samson AL, Tyebji S, Tonkin CJ, Bye CR, Turner BJ, Pepin G, Gantier MP, Rogers KL, McArthur K, Crouch PJ, Masters SL (2020) TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS. Cell 183:636–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu B, Xu MM, Fan C, Feng CL, Lu QK, Lu HM, Xiang CG, Bai F, Wang HY, Wu YW, Tang W (2022) STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion. Acta Pharmacol Sin 43:2055–2066

    Article  CAS  PubMed  Google Scholar 

  20. Woo MS, Mayer C, Binkle-Ladisch L, Sonner JK, Rosenkranz SC, Shaposhnykov A, Rothammer N, Tsvilovskyy V, Lorenz SM, Raich L, Bal LC, Vieira V, Wagner I, Bauer S, Glatzel M, Conrad M, Merkler D, Freichel M, Friese MA (2024) STING orchestrates the neuronal inflammatory stress response in multiple sclerosis. Cell 187:4043–4060

    Article  CAS  PubMed  Google Scholar 

  21. Wang B, Wang Y, Qiu J, Gao S, Yu S, Sun D, Lou H (2023) The STING inhibitor C-176 attenuates MPTP-induced neuroinflammation and neurodegeneration in mouse parkinsonian models. Int Immunopharmacol 124:110827

    Article  CAS  PubMed  Google Scholar 

  22. Siu T, Altman MD, Baltus GA, Childers M, Ellis JM, Gunaydin H, Hatch H, Ho T, Jewell J, Lacey BM, Lesburg CA, Pan BS, Sauvagnat B, Schroeder GK, Xu S (2019) Discovery of a novel cGAMP competitive ligand of the inactive form of STING. ACS Med Chem Lett 10:92–97

    Article  CAS  PubMed  Google Scholar 

  23. Li S, Hong Z, Wang Z, Li F, Mei J, Huang L, Lou X, Zhao S, Song L, Chen W, Wang Q, Liu H, Cai Y, Yu H, Xu H, Zeng G, Wang Q, Zhu J, Liu X, Tan N, Wang C (2018) The cyclopeptide astin C specifically inhibits the innate immune CDN sensor STING. Cell Rep 25:3405–3421

    Article  CAS  PubMed  Google Scholar 

  24. Hong Z, Mei J, Li C, Bai G, Maimaiti M, Hu H, Yu W, Sun L, Zhang L, Cheng D, Liao Y, Li S, You Y, Sun H, Huang J, Liu X, Lieberman J, Wang C (2021) STING inhibitors target the cyclic dinucleotide binding pocket. Proc Natl Acad Sci U S A 118:e2105465118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Guo F, Zhang J, Gao Y, Shu Z, Sun F, Ma J, Zhou X, Li W, Mao H, Lei X (2025) Discovery and total synthesis of anhydrotuberosin as a STING antagonist for treating autoimmune diseases. Angew Chem Int Ed Engl 64:e202407641

    Article  CAS  PubMed  Google Scholar 

  26. Barasa L, Chaudhuri S, Zhou JY, Jiang Z, Choudhary S, Green RM, Wiggin E, Cameron M, Humphries F, Fitzgerald KA, Thompson PR (2023) Development of LB244, an irreversible STING antagonist. J Am Chem Soc 145:20273–20288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hansen AL, Buchan GJ, Rühl M, Mukai K, Salvatore SR, Ogawa E, Andersen SD, Iversen MB, Thielke AL, Gunderstofte C, Motwani M, Møller CT, Jakobsen AS, Fitzgerald KA, Roos J, Lin R, Maier TJ, Goldbach-Mansky R, Miner CA, Qian W, Miner JJ, Rigby RE, Rehwinkel J, Jakobsen MR, Arai H, Taguchi T, Schopfer FJ, Olagnier D, Holm CK (2018) Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling. Proc Natl Acad Sci U S A 115:E7768–E7775

    Article  PubMed  PubMed Central  Google Scholar 

  28. Vinogradova EV, Zhang X, Remillard D, Lazar DC, Suciu RM, Wang Y, Bianco G, Yamashita Y, Crowley VM, Schafroth MA, Yokoyama M, Konrad DB, Lum KM, Simon GM, Kemper EK, Lazear MR, Yin S, Blewett MM, Dix MM, Nguyen N, Shokhirev MN, Chin EN, Lairson LL, Melillo B, Schreiber SL, Forli S, Teijaro JR, Cravatt BF (2020) An activity-guided map of electrophile-cysteine interactions in primary human T cells. Cell 182:1009–1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Niu GH, Hsiao WC, Lee PH, Zheng LG, Yang YS, Huang WC, Hsieh CC, Chiu TY, Wang JY, Chen CP, Huang CL, You MS, Kuo YP, Wang CM, Wen ZH, Yu GY, Chen CT, Chi YH, Tung CW, Hsu SC, Yeh TK, Sung PJ, Zhang MM, Tsou LK (2025) Orally bioavailable and site-selective covalent STING inhibitor derived from a macrocyclic marine diterpenoid. J Med Chem 8:5471–5487

    Article  Google Scholar 

  30. Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, Heymann M, van der Goot FG, Turcatti G, Behrendt R, Ablasser A (2018) Targeting STING with covalent small-molecule inhibitors. Nature 559:269–273

    Article  CAS  PubMed  Google Scholar 

  31. Shen A, Wang X, Chen Q, Zhang Y, Wang F, Li Y, Liu Z, Deng L, Ouyang W, Geng M, Song Z, Xie Z, Zhang A (2025) Discovery of potent STING inhibitors bearing a difluorobenzodioxol structural motif as potent anti-inflammatory agents. J Med Chem 68:8907–8932

    Article  CAS  PubMed  Google Scholar 

  32. Han X, Ma G, Peng R, Xu J, Sheng L, Liu H, Sui Q, Li J, Gu Y, Yu J, Feng Z, Xu Q, Wen X, Yuan H, Sun H, Dai L (2025) Discovery of an orally bioavailable STING inhibitor with in vivo anti-inflammatory activity in mice with STING-mediated inflammation. J Med Chem 68:2963–2980

    Article  CAS  PubMed  Google Scholar 

  33. Zhou X, Yue H, Wang X, Zang S, Li H, Yao S, Geng M, Zhan Z, Xie Z, Duan W (2025) Discovery of 3,4-dihydroisoquinoline-2(1H)-carboxamide STING inhibitors as anti-inflammatory agents. Eur J Med Chem 297:117922

    Article  CAS  PubMed  Google Scholar 

  34. Maekawa H, Inoue T, Ouchi H, Jao TM, Inoue R, Nishi H, Fujii R, Ishidate F, Tanaka T, Tanaka Y, Hirokawa N, Nangaku M, Inagi R (2019) Mitochondrial damage causes inflammation via cGAS-STING signaling in acute kidney injury. Cell Rep 29:1261–1273

    Article  CAS  PubMed  Google Scholar 

  35. Li Z, Mao C, Zhao Y, Zhao Y, Yi H, Liu J, Liang J (2025) The STING antagonist SN-011 ameliorates cisplatin induced acute kidney injury via suppression of STING/NF-κB-mediated inflammation. Int Immunopharmacol 146:113876

    Article  CAS  PubMed  Google Scholar 

  36. Ma R, Fu R, Wang Y, Njobvu KM, Fan Y, Yang Z, Chen M, Liu F, Jiang Z, Rao Y, Huang L, Xu C, Chen J, Liu J (2025) Discovery of novel rigid STING PROTAC degraders as potential therapeutics for acute kidney injury. Eur J Med Chem 290:117539

    Article  CAS  PubMed  Google Scholar 

  37. Reekie TA, Wilkinson SM, Law V, Hibbs DE, Ong JA, Kassiou M (2017) Rapid access to N-(indol-2-yl)amides and N-(indol-3-yl)amides as unexplored pharmacophores. Org Biomol Chem 15:576–580

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Shanghai Institute of Materia Medica, Chinese Academy of Sciences (no. SIMM0320231002), and the Shandong Laboratory Program (no. SYS202205) for their financial support.

Author information

Author notes

  1. Xiaoqian Zhou and Shumin Zang have contributed equally to this work.

Authors and Affiliations

  1. Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China

    Xiaoqian Zhou, Shanyan Yao, Hongfei Zhou, Zhengsheng Zhan & Wenhu Duan

  2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China

    Shumin Zang, Xiyuan Wang, Meiyu Geng & Zuoquan Xie

  3. Lingang Laboratory, Shanghai, 200031, People’s Republic of China

    Xiaoqian Zhou

  4. School of Physical Science & Technology, ShanghaiTech University, Shanghai, 201210, People’s Republic of China

    Xiaoqian Zhou

  5. University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China

    Shumin Zang, Hongfei Zhou, Meiyu Geng, Zhengsheng Zhan, Zuoquan Xie & Wenhu Duan

  6. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, People’s Republic of China

    Meiyu Geng

Authors
  1. Xiaoqian Zhou
    View author publications

    Search author on:PubMed Google Scholar

  2. Shumin Zang
    View author publications

    Search author on:PubMed Google Scholar

  3. Shanyan Yao
    View author publications

    Search author on:PubMed Google Scholar

  4. Hongfei Zhou
    View author publications

    Search author on:PubMed Google Scholar

  5. Xiyuan Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Meiyu Geng
    View author publications

    Search author on:PubMed Google Scholar

  7. Zhengsheng Zhan
    View author publications

    Search author on:PubMed Google Scholar

  8. Zuoquan Xie
    View author publications

    Search author on:PubMed Google Scholar

  9. Wenhu Duan
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Xiaoqian Zhou, Shanyan Yao, and Hongfei Zhou synthesized the compounds, conducted the molecular docking study, and prepared the manuscript. Shumin Zang and Xiyuan Wang performed the biological experiments, and also prepared the manuscript. Zhengsheng Zhan, Zuoquan Xie, Meiyu Geng, and Wenhu Duan designed and supervised this work, and reviewed the manuscript.

Corresponding authors

Correspondence to Zhengsheng Zhan, Zuoquan Xie or Wenhu Duan.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, X., Zang, S., Yao, S. et al. Discovery of isoindoline-2(1H)-carboxamide STING inhibitors as anti-inflammatory agents. Mol Divers (2025). https://doi.org/10.1007/s11030-025-11424-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1007/s11030-025-11424-y

Keywords

Profiles

  1. Zuoquan Xie View author profile