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NLRP3

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 1770

Nomenclature: NLRP3

Family: NOD-like receptor family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1036 1q44 NLRP3 NLR family pyrin domain containing 3
Mouse - 1033 11 B1.3 Nlrp3 NLR family, pyrin domain containing 3
Rat - - 10q22 Nlrp3 NLR family, pyrin domain containing 3
Previous and Unofficial Names Click here for help
AVP | C1orf7 | CIAS1 | NALP3 | AGTAVPRL | CLR1.1 | FCAS | FCU | MWS | AII | cold autoinflammatory syndrome 1 | Cryopyrin | NACHT, LRR and PYD domains-containing protein 3 | NLR family, pyrin domain containing 3 | PYPAF1 | NLR family
Database Links Click here for help
Alphafold Q96P20 (Hs), Q8R4B8 (Mm)
CATH/Gene3D 3.80.10.10
ChEMBL Target CHEMBL1741208 (Hs), CHEMBL3779755 (Mm)
Ensembl Gene ENSG00000162711 (Hs), ENSMUSG00000032691 (Mm), ENSRNOG00000003170 (Rn)
Entrez Gene 114548 (Hs), 216799 (Mm), 287362 (Rn)
Human Protein Atlas ENSG00000162711 (Hs)
KEGG Gene hsa:114548 (Hs), mmu:216799 (Mm), rno:287362 (Rn)
OMIM 606416 (Hs)
Pharos Q96P20 (Hs)
UniProtKB Q96P20 (Hs), Q8R4B8 (Mm)
Wikipedia NLRP3 (Hs)

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
oridonin Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.3 pKd 9
⤷ pKd 7.3 (Kd 5.25x10-8 M) [9]
Description: Equilibrium dissociation constant (KD) for oridonin binding to purified GFP-NLRP3.
compound 15z [PMID: 38029358] Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 7.0 pKd 18
⤷ pKd 7.0 (Kd 1.027x10-7 M) [18]
CY-09 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 6.3 pKd 13
⤷ pKd 6.3 (Kd 5x10-7 M) [13]
Description: MST assay for the affinity between CY-09 and purified GFP-NLRP3 protein.
NT-0796 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 9.5 pIC50 7
⤷ pIC50 9.5 (IC50 3.2x10-10 M) [7]
Description: Inhibition of IL-1β release from human PBMC
MCC950 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition >8.0 pIC50 2
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [2]
NT-0249 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 19
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [19]
Description: Inhibition of palmitate-driven IL-1β release from human PBMCs
NDT-19795 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 7
⤷ pIC50 7.2 (IC50 6.6x10-8 M) [7]
Description: Inhibition of IL-1β release from human PBMC
oridonin derivative 32 [PMID: 38751194] Small molecule or natural product Hs Inhibition 7.1 pIC50 8
⤷ pIC50 7.1 (IC50 7.72x10-8 M) [8]
compound 15z [PMID: 38029358] Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 6.9 pIC50 18
⤷ pIC50 6.9 (IC50 1.3x10-7 M) [18]
Description: Inhibition of NLRP3 activation
emlenoflast Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 6.8 pIC50 4
⤷ pIC50 6.8 (IC50 1.42x10-7 M) [4]
Description: Measuring inhibition of IL-1β production by LPS primed, ATP-activated human primary microglial cells
CP-424,174 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 6.6 pIC50 1
⤷ pIC50 6.6 (IC50 2.6x10-7 M) [1]
selnoflast Small molecule or natural product Immunopharmacology Ligand Hs Inhibition >6.0 pIC50 3
⤷ pIC50 >6.0 (IC50 <1x10-6 M) [3]
Description: Inhibition of IL-1β production from THP-1 monocytes or whole human blood
dapansutrile Small molecule or natural product Immunopharmacology Ligand Hs Inhibition - - 16
⤷ [16]
Description: As assessed by inhibition of recombinant NLRP3 ATPase activity by dapansutrile.
nibrozetone Small molecule or natural product Immunopharmacology Ligand Hs Inhibition - - 12
⤷ [12]
Agonist Comments
BMS-986299 is a clinical stage NLRP3 agonist that is being explored for anti-tumour activity [6].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
GDC-2394 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.3 pIC50 17
⤷ pIC50 7.3 (IC50 5.1x10-8 M) [17]
Description: Inhibition of NLRP3-induced caspase-1 activity in THP1 cells.
Immunopharmacology Comments
NLRP3 is a component of the NLRP3 inflammasome, a protein complex which activates caspase-1, and plays an important role in the regulation of inflammation and apoptosis (pyroptosis). Drug-like NLRP3 inhibitors are under investigation as novel therapeutics for the treatment of autoinflammatory diseases and neuroinflammation, as an alternative to anti-IL-1 therapies such as rilonacept, anakinra and canakinumab [1,14]. The potential of pharmacological modulation of the NLRP3 inflammasome as a mechanism to treat inflammatory diseases is reviewed by Mangan et al. (2018) [15].

NLRP3 inflammasome activation by tau in microglia has been demonstrated to drive amyloid-β pathology, including neuroinflammation and formation of neurofibrillary tangles [11].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Physiological Functions Comments
Involved in inflammasome formation and caspase-1 activation.
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Alzheimer disease
Synonyms: Alzheimer's disease [Disease Ontology: DOID:10652]
Disease Ontology: DOID:10652
OMIM: 104300
Disease:  Atherosclerosis susceptibility
Disease Ontology: DOID:1936
OMIM: 108725
Disease:  CINCA syndrome
Synonyms: Chronic infantile neurological cutaneous articular syndrome
OMIM: 607115
Orphanet: ORPHA1451
Disease:  Diabetes mellitus, noninsulin-dependent; NIDDM
Synonyms: Diabetes mellitus, Type II; T2D [OMIM: 125853]
Maturity onset diabetes
Type 2 diabetes mellitus [Disease Ontology: DOID:9352]
Disease Ontology: DOID:9352
OMIM: 125853
Disease:  Familial cold autoinflammatory syndrome 1; FCAS1
Synonyms: Familial cold urticaria [Orphanet: ORPHA47045]
OMIM: 120100
Orphanet: ORPHA47045
Disease:  Gout
Disease Ontology: DOID:13189
Disease:  Inflammatory bowel disease
Synonyms: Inflammatory bowel disease [Disease Ontology: DOID:0050589]
Disease Ontology: DOID:0050589
OMIM: 266600
Disease:  Muckle-Wells syndrome
Description: Muckle–Wells syndrome (MWS) is a rare autosomal dominant disease which causes sensorineural deafness, recurrent hives, and can lead to amyloidosis.
Synonyms: CAPS2
cryopyrin-associated periodic syndrome 2
MWS
urticaria-deafness-amyloidosis syndrome
OMIM: 191900
Orphanet: ORPHA575
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human R260W 778C>T 5
Missense Human A352V 1055C>T 10
Missense Human G569R 1705G>C 5
Biologically Significant Variants Click here for help
Type:  Naturally occurring mutation
Species:  Human
Nucleotide change:  C/T
Amino acids:  260
SNP accession:  rs121908150
References:  5
Type:  Naturally occurring mutation
Species:  Human
Nucleotide change:  C/T
Amino acids:  352
SNP accession:  rs121908149
References:  10
Type:  Naturally occurring mutation
Species:  Human
Nucleotide change:  G/C
Amino acids:  569
SNP accession:  rs121908151
References:  5

References

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1. Baldwin AG, Brough D, Freeman S. (2016) Inhibiting the Inflammasome: A Chemical Perspective. J Med Chem, 59 (5): 1691-710. [PMID:26422006]

2. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A et al.. (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med, 21 (3): 248-55. [PMID:25686105]

3. Cooper M, Miller D, Macleod A, Van Wiltenburg J, Thom S, St-Gallay S, Shannon J. (2019) Novel sulfonamide carboxamide compounds. Patent number: WO2019008025A1. Assignee: Inflazome Limited. Priority date: 07/07/2017. Publication date: 10/01/2019.

4. Cooper M, O'Neill L. (2021) Treatment or prevention of psychiatric brain disorders using the nlrp3 inhibitor n-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1 -isopropyl-1 h-pyrazole-3-sulfonamide. Patent number: WO2021089781A1. Assignee: Inflazome Limited. Priority date: 07/11/2019. Publication date: 14/05/2021.

5. Dodé C, Le Dû N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, Meyrier A, Watts RA, Scott DG, Nicholls A et al.. (2002) New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet, 70 (6): 1498-506. [PMID:11992256]

6. Glick G, Ghosh S, Roush WR, Olhava EJ, O'Malley D. (2018) Substituted imidazo-quinolines as nlrp3 modulators. Patent number: WO2018152396A1. Assignee: Innate Tumor Immunity Inc.. Priority date: 17/02/2017. Publication date: 23/08/2018.

7. Harrison D, Billinton A, Bock MG, Doedens JR, Gabel CA, Holloway MK, Porter RA, Reader V, Scanlon J, Schooley K et al.. (2023) Discovery of Clinical Candidate NT-0796, a Brain-Penetrant and Highly Potent NLRP3 Inflammasome Inhibitor for Neuroinflammatory Disorders. J Med Chem, 66 (21): 14897-14911. [PMID:37874905]

8. He C, Liu J, Li J, Wu H, Jiao C, Ze X, Xu S, Zhu Z, Guo W, Xu J et al.. (2024) Hit-to-Lead Optimization of the Natural Product Oridonin as Novel NLRP3 Inflammasome Inhibitors with Potent Anti-Inflammation Activity. J Med Chem, 67 (11): 9406-9430. [PMID:38751194]

9. He H, Jiang H, Chen Y, Ye J, Wang A, Wang C, Liu Q, Liang G, Deng X, Jiang W et al.. (2018) Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat Commun, 9 (1): 2550. [PMID:29959312]

10. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. (2001) Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet, 29 (3): 301-5. [PMID:11687797]

11. Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D et al.. (2019) NLRP3 inflammasome activation drives tau pathology. Nature, 575 (7784): 669-673. [PMID:31748742]

12. Jayabalan N, Oronsky B, Cabrales P, Reid T, Caroen S, Johnson AM, Birch NA, O'Sullivan JD, Gordon R. (2023) A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation. Drugs, 83 (5): 389-402. [PMID:36920652]

13. Jiang H, He H, Chen Y, Huang W, Cheng J, Ye J, Wang A, Tao J, Wang C, Liu Q et al.. (2017) Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med, 214 (11): 3219-3238. [PMID:29021150]

14. Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. (2018) Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov, 17 (9): 688. [PMID:30116046]

15. Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. (2018) Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov, 17 (8): 588-606. [PMID:30026524]

16. Marchetti C, Swartzwelter B, Gamboni F, Neff CP, Richter K, Azam T, Carta S, Tengesdal I, Nemkov T, D'Alessandro A et al.. (2018) OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci USA, 115 (7): E1530-E1539. [PMID:29378952]

17. McBride C, Trzoss L, Povero D, Lazic M, Ambrus-Aikelin G, Santini A, Pranadinata R, Bain G, Stansfield R, Stafford JA et al.. (2022) 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 (21): 14721-14739. [PMID:36279149]

18. Sun S, Li Z, Huang C, Liu J, Yu Q, Jiang X, Yue K, Zhao J, Xu T, Liu Y et al.. (2023) Discovery of Novel 2,3-Dihydro-1H-indene-5-sulfonamide NLRP3 Inflammasome Inhibitors Targeting Colon as a Potential Therapy for Colitis. J Med Chem, 66 (23): 16141-16167. [PMID:38029358]

19. Thornton P, Reader V, Digby Z, Smolak P, Lindsay N, Harrison D, Clarke N, Watt AP. (2024) Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796. J Pharmacol Exp Ther, 388 (3): 813-826. [PMID:38336379]

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