Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT4EN8X)

• DTT Name: Caterpiller protein 1.1 (NLRP3)
• Synonyms: PYRIN-containing APAF1-like protein 1; PYPAF1; NALP3; NACHT, LRR and PYD domains-containing protein 3; Cryopyrin; Cold-induced autoinflammatory syndrome 1 protein; CLR1.1; CIAS1; C1orf7; Angiotensin/vasopressin receptor AII/AVP-like
• Gene Name: NLRP3
• DTT Type: Clinical trial target; [1]
• UniProt ID: NLRP3_HUMAN
• TTD ID: T08499
• Sequence:
  MKMASTRCKLARYLEDLEDVDLKKFKMHLEDYPPQKGCIPLPRGQTEKADHVDLATLMID
  FNGEEKAWAMAVWIFAAINRRDLYEKAKRDEPKWGSDNARVSNPTVICQEDSIEEEWMGL
  LEYLSRISICKMKKDYRKKYRKYVRSRFQCIEDRNARLGESVSLNKRYTRLRLIKEHRSQ
  QEREQELLAIGKTKTCESPVSPIKMELLFDPDDEHSEPVHTVVFQGAAGIGKTILARKMM
  LDWASGTLYQDRFDYLFYIHCREVSLVTQRSLGDLIMSCCPDPNPPIHKIVRKPSRILFL
  MDGFDELQGAFDEHIGPLCTDWQKAERGDILLSSLIRKKLLPEASLLITTRPVALEKLQH
  LLDHPRHVEILGFSEAKRKEYFFKYFSDEAQARAAFSLIQENEVLFTMCFIPLVCWIVCT
  GLKQQMESGKSLAQTSKTTTAVYVFFLSSLLQPRGGSQEHGLCAHLWGLCSLAADGIWNQ
  KILFEESDLRNHGLQKADVSAFLRMNLFQKEVDCEKFYSFIHMTFQEFFAAMYYLLEEEK
  EGRTNVPGSRLKLPSRDVTVLLENYGKFEKGYLIFVVRFLFGLVNQERTSYLEKKLSCKI
  SQQIRLELLKWIEVKAKAKKLQIQPSQLELFYCLYEMQEEDFVQRAMDYFPKIEINLSTR
  MDHMVSSFCIENCHRVESLSLGFLHNMPKEEEEEEKEGRHLDMVQCVLPSSSHAACSHGL
  VNSHLTSSFCRGLFSVLSTSQSLTELDLSDNSLGDPGMRVLCETLQHPGCNIRRLWLGRC
  GLSHECCFDISLVLSSNQKLVELDLSDNALGDFGIRLLCVGLKHLLCNLKKLWLVSCCLT
  SACCQDLASVLSTSHSLTRLYVGENALGDSGVAILCEKAKNPQCNLQKLGLVNSGLTSVC
  CSALSSVLSTNQNLTHLYLRGNTLGDKGIKLLCEGLLHPDCKLQVLELDNCNLTSHCCWD
  LSTLLTSSQSLRKLSLGNNDLGDLGVMMFCEVLKQQSCLLQNLGLSEMYFNYETKSALET
  LQEEKPELTVVFEPSW
• Function: In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1 (and possibly CASP4 and CASP5). Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP3 inflammasome is also required for HMGB1 secretion. The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation stimuli include extracellular ATP, reactive oxygen species, K(+) efflux, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, cytosolic dsRNA, etc. However, it is unclear what constitutes the direct NLRP3 activator. Activation in presence of cytosolic dsRNA is mediated by DHX33. Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth. During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription. Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF. As the sensor component of the NLRP3 inflammasome, plays a crucial role in innate immunity and inflammation.
• KEGG Pathway:
  Necroptosis (hsa04217)
  NOD-like receptor signaling pathway (hsa04621)
  C-type lectin receptor signaling pathway (hsa04625)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Yersinia infection (hsa05135)
  Influenza A (hsa05164)
  Coronavirus disease - COVID-19 (hsa05171)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  The NLRP3 inflammasome (R-HSA-844456)
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  Metalloprotease DUBs (R-HSA-5689901)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dapansutrile	DM7IH48	Acute gout flare	FA25.0	Phase 2	[1]
BMS-986299	DMTMUWJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]
Selnoflast	DM4NKNK	Inflammation	1A00-CA43.1	Phase 1	[3]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MCC950	DM6J2UZ	Discovery agent	N.A.	Investigative	[4]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] National Cancer Institute Drug Dictionary (drug name BMS-986299).
• [3] Clinical pipeline report, company report or official report of Roche
• [4] A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015 Mar;21(3):248-55.