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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

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
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
UniProtKB
Wikipedia

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
CY-09 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 6.3 pKd 9
pKd 6.3 (Kd 5x10-7 M) [9]
Description: MST assay for the affinity between CY-09 and purified GFP-NLRP3 protein.
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]
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 - - 12
[12]
Description: As assessed by inhibition of recombinant NLRP3 ATPase activity by dapansutrile.
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 Immunopharmacology Ligand Hs Inhibition 7.3 pIC50 13
pIC50 7.3 (IC50 5.1x10-8 M) [13]
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 [1,10]. The potential of pharmacological modulation of the NLRP3 inflammasome as a mechanism to treat inflammatory diseases is reviewed by Mangan et al. (2018) [11].

NLRP3 inflammasome activation by tau in microglia has been demonstrated to drive amyloid-β pathology, including neuroinflammation and formation of neurofibrillary tangles [8].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 9 GO processes
GO:0002221 pattern recognition receptor signaling pathway IC
GO:0002674 negative regulation of acute inflammatory response IMP
GO:0006954 inflammatory response IMP
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
GO:0050727 regulation of inflammatory response IBA
GO:0050728 negative regulation of inflammatory response IMP
GO:0050729 positive regulation of inflammatory response IC
GO:2000553 positive regulation of T-helper 2 cell cytokine production ISS
click arrow to show/hide IEA associations
GO:0045087 innate immune response IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
GO:2000553 positive regulation of T-helper 2 cell cytokine production ISS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:2000553 positive regulation of T-helper 2 cell cytokine production ISS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 8 GO processes
GO:0002221 pattern recognition receptor signaling pathway IC
GO:0002674 negative regulation of acute inflammatory response IMP
GO:0002830 positive regulation of type 2 immune response ISS
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
GO:0050727 regulation of inflammatory response IBA
GO:0050728 negative regulation of inflammatory response IMP
GO:0050729 positive regulation of inflammatory response IC
GO:2000553 positive regulation of T-helper 2 cell cytokine production ISS
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 4 GO processes
GO:0032691 negative regulation of interleukin-1 beta production IMP
GO:0032731 positive regulation of interleukin-1 beta production IDA
GO:0032753 positive regulation of interleukin-4 production ISS
GO:2000553 positive regulation of T-helper 2 cell cytokine production ISS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes
GO:0002221 pattern recognition receptor signaling pathway IC
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
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 7
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: 
References:  5
Type:  Naturally occurring mutation
Species:  Human
Nucleotide change:  C/T
Amino acids:  352
SNP accession: 
References:  7
Type:  Naturally occurring mutation
Species:  Human
Nucleotide change:  G/C
Amino acids:  569
SNP accession: 
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. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

Contributors

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