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Cited by 28Inflammasome and immune disordersImmune Response and InflammationAutoimmune and Inflammatory Disorders Research

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JT002, a small molecule inhibitor of the NLRP3 inflammasome for the treatment of autoinflammatory disorders

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Ambrus-Aikelin, Geza, Takeda, Katsuyuki, Joetham, Anthony, Lazic, Milos, Povero, Davide, Santini, Angelina M., Pranadinata, Rama, Johnson, Casey D., McGeough, Matthew D., Beasley, Federico C., Stansfield, Ryan, McBride, Christopher, Trzoss, Lynnie, Hoffman, Hal M., Feldstein, Ariel E., Stafford, Jeffrey A., Veal, James M., Bain, Gretchen, Gelfand, Erwin W.·2023·Scientific Reports
DOI 10.1038/s41598-023-39805-zPMC PMC10439952

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Abstract

The NLRP3 inflammasome is an intracellular, multiprotein complex that promotes the auto-catalytic activation of caspase-1 and the subsequent maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18. Persistent activation of the NLRP3 inflammasome has been implicated in the pathophysiology of a number of inflammatory and autoimmune diseases, including neuroinflammation, cardiovascular disease, non-alcoholic steatohepatitis, lupus nephritis and severe asthma. Here we describe the preclinical profile of JT002, a novel small molecule inhibitor of the NLRP3 inflammasome. JT002 potently reduced NLRP3-dependent proinflammatory cytokine production across a number of cellular assays and prevented pyroptosis, an inflammatory form of cell death triggered by active caspase-1. JT002 demonstrated in vivo target engagement at therapeutically relevant concentrations when orally dosed in mice and prevented body weight loss and improved inflammatory and fibrotic endpoints in a model of Muckle–Wells syndrome (MWS). In two distinct models of neutrophilic airway inflammation, JT002 treatment significantly reduced airway hyperresponsiveness and airway neutrophilia. These results provide a rationale for the therapeutic targeting of the NLRP3 inflammasome in severe asthma and point to the use of JT002 in a variety of inflammatory disorders.

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  • Inhibition of NLRP3 activation in myeloid cells demonstrated promising anti-fibrotic effects in murine models.

    “Similarly, while inhibition of inflammasome signaling, particularly NLRP3 activation in myeloid cells, demonstrated promising anti-fibrotic effects in murine models (142–144)”

    From Targeting macrophages in liver fibrosis (2026) · cites this paper as [144]

    The Results section on the Muckle–Wells mouse model reports reduced hepatic collagen and stellate-cell activation after JT002 treatment, supporting an anti-fibrotic effect in mice. The paper also shows NLRP3 inhibition in mouse macrophages, but it does not establish that the anti-fibrotic effect resulted specifically from inhibition in myeloid cells; the fibrosis finding comes from one murine model, not multiple models. No page numbers are available in our copy. (LLM, conf=0.86)

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Research works printed but not linked: 52

  1. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832. https://doi.org/10.1016/j.cell.2010.01.040 (2010). · DOI · Paper page
  2. Guo, H., Callaway, J. B. & Ting, J. P. Inflammasomes: Mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687. https://doi.org/10.1038/nm.3893 (2015). · DOI · Paper page
  3. Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022. https://doi.org/10.1016/j.cell.2014.04.007 (2014). · DOI
  4. Liu, X. & Lieberman, J. Advances in Immunology Vol. 135, 81–117 (Academic Press, 2017).
  5. England, H., Summersgill, H. R., Edye, M. E., Rothwell, N. J. & Brough, D. Release of interleukin-1alpha or interleukin-1beta depends on mechanism of cell death. J. Biol. Chem. 289, 15942–15950. https://doi.org/10.1074/jbc.M114.557561 (2014). · DOI
  6. Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121. https://doi.org/10.1038/nature10558 (2011). · DOI · Paper page
  7. He, Y., Hara, H. & Nunez, G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci. 41, 1012–1021. https://doi.org/10.1016/j.tibs.2016.09.002 (2016). · DOI · Paper page
  8. Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671. https://doi.org/10.1038/nature15541 (2015). · DOI · Paper page
  9. Gaidt, M. M. et al. Human monocytes engage an alternative inflammasome pathway. Immunity 44, 833–846. https://doi.org/10.1016/j.immuni.2016.01.012 (2016). · DOI
  10. Hoffman, H. M. & Broderick, L. The role of the inflammasome in patients with autoinflammatory diseases. J. Allergy Clin. Immunol. 138, 3–14. https://doi.org/10.1016/j.jaci.2016.05.001 (2016). · DOI
  11. Aksentijevich, I. et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 46, 3340–3348. https://doi.org/10.1002/art.10688 (2002). · DOI
  12. Brydges, S. D. et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30, 875–887. https://doi.org/10.1016/j.immuni.2009.05.005 (2009). · DOI · Paper page
  13. Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat. Genet. 29, 301–305. https://doi.org/10.1038/ng756 (2001). · DOI
  14. Mangan, M. S. J. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Discov. 17, 588–606. https://doi.org/10.1038/nrd.2018.97 (2018). · DOI · Paper page
  15. Vande Walle, L. et al. Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature 512, 69–73. https://doi.org/10.1038/nature13322 (2014). · DOI
  16. Paramel, G. V., Sirsjo, A. & Fransen, K. Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease. Mediat. Inflamm. 2015, 846782. https://doi.org/10.1155/2015/846782 (2015). · DOI
  17. Lee, Y. H. & Bae, S. C. Association between functional NLRP3 polymorphisms and susceptibility to autoimmune and inflammatory diseases: A meta-analysis. Lupus 25, 1558–1566. https://doi.org/10.1177/0961203316644336 (2016). · DOI
  18. Fu, R. et al. Podocyte Activation of NLRP3 inflammasomes contributes to the development of proteinuria in lupus nephritis. Arthritis Rheumatol. 69, 1636–1646. https://doi.org/10.1002/art.40155 (2017). · DOI
  19. Lu, A. et al. Hyperactivation of the NLRP3 inflammasome in myeloid cells leads to severe organ damage in experimental lupus. J. Immunol. 198, 1119–1129. https://doi.org/10.4049/jimmunol.1600659 (2017). · DOI
  20. Major, T. J., Dalbeth, N., Stahl, E. A. & Merriman, T. R. An update on the genetics of hyperuricaemia and gout. Nat. Rev. Rheumatol. 14, 341–353. https://doi.org/10.1038/s41584-018-0004-x (2018). · DOI
  21. Blasetti Fantauzzi, C. et al. Deficiency of the purinergic receptor 2X7 attenuates nonalcoholic steatohepatitis induced by high-fat diet: Possible role of the NLRP3 inflammasome. Oxid. Med. Cell Longev. 2017, 8962458. https://doi.org/10.1155/2017/8962458 (2017). · DOI
  22. Wree, A. et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 59, 898–910. https://doi.org/10.1002/hep.26592 (2014). · DOI · Paper page
  23. Dempsey, C. et al. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-beta and cognitive function in APP/PS1 mice. Brain Behav. Immun. 61, 306–316. https://doi.org/10.1016/j.bbi.2016.12.014 (2017). · DOI · Paper page
  24. Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678. https://doi.org/10.1038/nature11729 (2013). · DOI · Paper page
  25. Malhotra, S. et al. NLRP3 inflammasome is associated with the response to IFN-beta in patients with multiple sclerosis. Brain 138, 644–652. https://doi.org/10.1093/brain/awu388 (2015). · DOI
  26. Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255. https://doi.org/10.1038/nm.3806 (2015). · DOI · Paper page
  27. McKenzie, B. A. et al. Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. Proc. Natl. Acad. Sci. U.S.A. https://doi.org/10.1073/pnas.1722041115 (2018). · DOI
  28. Furlan, R. et al. Caspase-1 regulates the inflammatory process leading to autoimmune demyelination. J. Immunol. 163, 2403–2409 (1999). · DOI
  29. Gris, D. et al. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J. Immunol. 185, 974–981. https://doi.org/10.4049/jimmunol.0904145 (2010). · DOI · Paper page
  30. Shaw, P. J. et al. Cutting edge: Critical role for PYCARD/ASC in the development of experimental autoimmune encephalomyelitis. J. Immunol. 184, 4610–4614. https://doi.org/10.4049/jimmunol.1000217 (2010). · DOI
  31. van Hout, G. P. et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur. Heart J. 38, 828–836. https://doi.org/10.1093/eurheartj/ehw247 (2017). · DOI
  32. Sandanger, O. et al. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc. Res. 99, 164–174. https://doi.org/10.1093/cvr/cvt091 (2013). · DOI
  33. Primiano, M. J. et al. Efficacy and pharmacology of the NLRP3 inflammasome inhibitor CP-456,773 (CRID3) in murine models of dermal and pulmonary inflammation. J. Immunol. 197, 2421–2433. https://doi.org/10.4049/jimmunol.1600035 (2016). · DOI
  34. Kim, R. Y. et al. Role for NLRP3 inflammasome-mediated, IL-1beta-dependent responses in severe, steroid-resistant asthma. Am. J. Respir. Crit. Care Med. 196, 283–297. https://doi.org/10.1164/rccm.201609-1830OC (2017). · DOI
  35. Riteau, N. et al. Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am. J. Respir. Crit. Care Med. 182, 774–783. https://doi.org/10.1164/rccm.201003-0359OC (2010). · DOI · Paper page
  36. Guo, C. et al. NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. Clin. Exp. Immunol. 194, 231–243. https://doi.org/10.1111/cei.13167 (2018). · DOI
  37. Perera, A. P. et al. MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice. Sci. Rep. 8, 8618. https://doi.org/10.1038/s41598-018-26775-w (2018). · DOI
  38. Simpson, J. L. et al. Elevated expression of the NLRP3 inflammasome in neutrophilic asthma. Eur. Respir. J. 43, 1067–1076. https://doi.org/10.1183/09031936.00105013 (2014). · DOI
  39. Rossios, C. et al. Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma. J. Allergy Clin. Immunol. 141, 560–570. https://doi.org/10.1016/j.jaci.2017.02.045 (2018). · DOI
  40. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: Guardians of the body. Annu. Rev. Immunol. 27, 229–265. https://doi.org/10.1146/annurev.immunol.021908.132715 (2009). · DOI · Paper page
  41. Boucher, D. et al. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity. J. Exp. Med. 215, 827–840. https://doi.org/10.1084/jem.20172222 (2018). · DOI
  42. Nanthakumar, C. B. et al. Dissecting fibrosis: Therapeutic insights from the small-molecule toolbox. Nat. Rev. Drug Discov. 14, 693–720. https://doi.org/10.1038/nrd4592 (2015). · DOI
  43. Ii, M. et al. A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol. Pharmacol. 69, 1288–1295. https://doi.org/10.1124/mol.105.019695 (2006). · DOI
  44. Grinstein, L. et al. An optimized whole blood assay measuring expression and activity of NLRP3, NLRC4 and AIM2 inflammasomes. Clin. Immunol. 191, 100–109. https://doi.org/10.1016/j.clim.2017.11.011 (2018). · DOI
  45. Joetham, A. et al. Inducible and naturally occurring regulatory T cells enhance lung allergic responses through divergent transcriptional pathways. J. Allergy Clin. Immunol. 139, 1331–1342. https://doi.org/10.1016/j.jaci.2016.06.051 (2017). · DOI
  46. Matsubara, S. et al. Vgamma1+ T cells and tumor necrosis factor-alpha in ozone-induced airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol. 40, 454–463. https://doi.org/10.1165/rcmb.2008-0346OC (2009). · DOI
  47. Schett, G., Dayer, J. M. & Manger, B. Interleukin-1 function and role in rheumatic disease. Nat. Rev. Rheumatol. 12, 14–24. https://doi.org/10.1038/nrrheum.2016.166 (2016). · DOI
  48. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131. https://doi.org/10.1056/NEJMoa1707914 (2017). · DOI · Paper page
  49. Shah, F. et al. Setting clinical exposure levels of concern for drug-induced liver injury (DILI) using mechanistic in vitro assays. Toxicol. Sci. 147, 500–514. https://doi.org/10.1093/toxsci/kfv152 (2015). · DOI · Paper page
  50. Chen, M., Borlak, J. & Tong, W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology 58, 388–396. https://doi.org/10.1002/hep.26208 (2013). · DOI · Paper page
  51. Peterson, L. A. Electrophilic intermediates produced by bioactivation of furan. Drug Metab. Rev. 38, 615–626. https://doi.org/10.1080/03602530600959417 (2006). · DOI
  52. McBride, C. et al. Overcoming preclinical safety obstacles to discover (S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (GDC-2394): A potent and selective NLRP3 inhibitor. J. Med. Chem. 65, 14721–14739. https://doi.org/10.1021/acs.jmedchem.2c01250 (2022). · DOI

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Authors
Ambrus-Aikelin, G., Takeda, K., Joetham, A., Lazic, M., Povero, D., Santini, A. M., Pranadinata, R., Johnson, C. D., McGeough, M. D., Beasley, F. C., Stansfield, R., McBride, C., Trzoss, L., Hoffman, H. M., Feldstein, A. E., Stafford, J. A., Veal, J. M., Bain, G., & Gelfand, E. W.
Affiliations
  • National Jewish Health (US)
  • Mayo Clinic (US)
  • University of California San Diego (US)
Corresponding author
Povero, Davide
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2023-08-19
Volume
13
Issue
1
Pages
13524-13524
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-023-39805-z
PMC
PMC10439952
OpenAlex
W4386001332
Cited by
28
References
3
Citations by year
2026: 9 · 2025: 8 · 2024: 8 · 2023: 3
FWCI
2.50
Type
journal article
Language
en
Update notices
correction (2023-11-16)
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Genentech
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
Keywords
NLRP3 inflammasome, small molecule inhibitors, autoinflammatory disease, Muckle-Wells syndrome, severe asthma, neutrophilic airway inflammation, pyroptosis, caspase-1, IL-1β, IL-18, airway hyperresponsiveness, airway neutrophilia, fibrosis, target engagement, oral administration
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Cardiovascular Diseases, Lupus Nephritis, Caspase 1, Mice, Inflammasomes

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