Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTQR74A)

• DTT Name: Proteinase activated receptor 2 (PAR2)
• Synonyms: Thrombin receptor-like 1; Proteinase-activated receptor-2; Proteinase-activated receptor 2; Protease activated receptor 2; PAR-2; GPR11; G-protein coupled receptor 11; Coagulation factor II receptor-like 1
• Gene Name: F2RL1
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: PAR2_HUMAN
• TTD ID: T62841
• Sequence:
  MRSPSAAWLLGAAILLAASLSCSGTIQGTNRSSKGRSLIGKVDGTSHVTGKGVTVETVFS
  VDEFSASVLTGKLTTVFLPIVYTIVFVVGLPSNGMALWVFLFRTKKKHPAVIYMANLALA
  DLLSVIWFPLKIAYHIHGNNWIYGEALCNVLIGFFYGNMYCSILFMTCLSVQRYWVIVNP
  MGHSRKKANIAIGISLAIWLLILLVTIPLYVVKQTIFIPALNITTCHDVLPEQLLVGDMF
  NYFLSLAIGVFLFPAFLTASAYVLMIRMLRSSAMDENSEKKRKRAIKLIVTVLAMYLICF
  TPSNLLLVVHYFLIKSQGQSHVYALYIVALCLSTLNSCIDPFVYYFVSHDFRDHAKNALL
  CRSVRTVKQMQVSLTSKKHSRKSSSYSSSSTTVKTSY
• Function: Its function is mediated through the activation of several signaling pathways including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-kappaB and Rho. Can also be transactivated by cleaved F2R/PAR1. Involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, and acts as a sensor for proteolytic enzymes generated during infection. Generally is promoting inflammation. Can signal synergistically with TLR4 and probably TLR2 in inflammatory responses and modulates TLR3 signaling. Has a protective role in establishing the endothelial barrier; the activity involves coagulation factor X. Regulates endothelial cell barrier integrity during neutrophil extravasation, probably following proteolytic cleavage by PRTN3. Proposed to have a bronchoprotective role in airway epithelium, but also shown to compromise the airway epithelial barrier by interrupting E-cadherin adhesion. Involved in the regulation of vascular tone; activation results in hypotension presumably mediated by vasodilation. Associates with a subset of G proteins alpha subunits such as GNAQ, GNA11, GNA14, GNA12 and GNA13, but probably not with G(o) alpha, G(i) subunit alpha-1 and G(i) subunit alpha-2. However, according to can signal through G(i) subunit alpha. Believed to be a class B receptor which internalizes as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptor, for extended periods of time. Mediates inhibition of TNF-alpha stimulated JNK phosphorylation via coupling to GNAQ and GNA11; the function involves dissociation of RIPK1 and TRADD from TNFR1. Mediates phosphorylation of nuclear factor NF-kappa-B RELA subunit at 'Ser-536'; the function involves IKBKB and is predominantly independent of G proteins. Involved in cellular migration. Involved in cytoskeletal rearrangement and chemotaxis through beta-arrestin-promoted scaffolds; the function is independent of GNAQ and GNA11 and involves promotion of cofilin dephosphorylation and actin filament severing. Induces redistribution of COPS5 from the plasma membrane to the cytosol and activation of the JNK cascade is mediated by COPS5. Involved in the recruitment of leukocytes to the sites of inflammation and is the major PAR receptor capable of modulating eosinophil function such as proinflammatory cytokine secretion, superoxide production and degranulation. During inflammation promotes dendritic cell maturation, trafficking to the lymph nodes and subsequent T-cell activation. Involved in antimicrobial response of innate immnune cells; activation enhances phagocytosis of Gram-positive and killing of Gram-negative bacteria. Acts synergistically with interferon-gamma in enhancing antiviral responses. Implicated in a number of acute and chronic inflammatory diseases such as of the joints, lungs, brain, gastrointestinal tract, periodontium, skin, and vascular systems, and in autoimmune disorders. Receptor for trypsin and trypsin-like enzymes coupled to G proteins.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  African trypanosomiasis (hsa05143)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MEDI0618	DM7GNSY	Osteoarthritis pain	MG30.31	Phase 1	[2]

35 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amidine compound 1	DMUPT9A	Inflammation	1A00-CA43.1	Patented	[1]
Amidine compound 2	DM2UWSX	Inflammation	1A00-CA43.1	Patented	[1]
Amidine compound 3	DMV0QJ4	Inflammation	1A00-CA43.1	Patented	[1]
Amidine compound 4	DM9EGVN	Inflammation	1A00-CA43.1	Patented	[1]
Amidine compound 5	DMMN8OY	Inflammation	1A00-CA43.1	Patented	[1]
Amidine compound 6	DMFNK0L	Inflammation	1A00-CA43.1	Patented	[1]
Benzimidazole derivative 10	DML3PE4	N. A.	N. A.	Patented	[1]
Benzimidazole derivative 8	DMQ75BN	N. A.	N. A.	Patented	[1]
Benzimidazole derivative 9	DMHJ98M	N. A.	N. A.	Patented	[1]
Benzothiazine-carboxamide compound 1	DMJ51VZ	Skin inflammation	EF20.Y	Patented	[1]
Benzothiazine-carboxamide compound 2	DMMP2RT	Skin inflammation	EF20.Y	Patented	[1]
Benzothiazine-carboxamide compound 3	DMI31OD	Skin inflammation	EF20.Y	Patented	[1]
Benzothiazine-carboxamide compound 4	DMSR918	Skin inflammation	EF20.Y	Patented	[1]
Benzothiazine-carboxamide compound 5	DMM7N5E	Skin inflammation	EF20.Y	Patented	[1]
Benzothiazine-carboxamide compound 6	DMW94IQ	Skin inflammation	EF20.Y	Patented	[1]
Imidazopyridazine derivative 3	DMXVOP3	Inflammation	1A00-CA43.1	Patented	[1]
Imidazopyridazine derivative 4	DMIAJMO	Inflammation	1A00-CA43.1	Patented	[1]
Imidazopyridazine derivative 5	DM9SXYH	Inflammation	1A00-CA43.1	Patented	[1]
Imidazopyridazine derivative 6	DM5F1LR	Inflammation	1A00-CA43.1	Patented	[1]
Imidazopyridazine derivative 7	DM5X160	Inflammation	1A00-CA43.1	Patented	[1]
Imidazopyridazine derivative 8	DMF7NXJ	Inflammation	1A00-CA43.1	Patented	[1]
Peptide analog 71	DMSEKZG	N. A.	N. A.	Patented	[1]
Peptide analog 72	DMXU71M	N. A.	N. A.	Patented	[1]
Peptidomimetic analog 6	DMSUD5X	N. A.	N. A.	Patented	[1]
Piperazine derivative 5	DMDFUBH	Atopic dermatitis	EA80	Patented	[1]
Piperazine urea derivative 3	DMNAJWQ	Inflammation	1A00-CA43.1	Patented	[1]
Piperazine urea derivative 4	DM3K7IM	Inflammation	1A00-CA43.1	Patented	[1]
Piperidine derivative 2	DMHXMB4	Inflammation	1A00-CA43.1	Patented	[1]
Piperidine derivative 3	DM80XRM	Inflammation	1A00-CA43.1	Patented	[1]
PMID26936077-Compound-13	DMXK6LV	Gastric ulcer	DA60	Patented	[1]
PMID26936077-Compound-34	DMIZL8D	Gastric ulcer	DA60	Patented	[1]
Quinazoline derivative 10	DMZ3ORT	Chronic obstructive pulmonary disease	CA22	Patented	[1]
Quinazoline derivative 11	DMAH435	Chronic obstructive pulmonary disease	CA22	Patented	[1]
Quinazoline derivative 12	DMVKZU2	Chronic obstructive pulmonary disease	CA22	Patented	[1]
Quinazoline derivative 13	DMFU6OD	Arteriosclerosis	BD40	Patented	[1]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ASKH95	DM2DPYQ	Discovery agent	N.A.	Investigative	[3]
GB110	DMWFYJ4	Discovery agent	N.A.	Investigative	[4]
GB88	DMLDVFM	Discovery agent	N.A.	Investigative	[5]

References

• [1] Protease activated receptor 2 (PAR2) modulators: a patent review (2010-2015).Expert Opin Ther Pat. 2016;26(4):471-83.
• [2] Clinical pipeline report, company report or official report of AstraZeneca
• [3] Essential role for proteinase-activated receptor-2 in arthritis. J Clin Invest. 2003 Jan;111(1):35-41.
• [4] Novel agonists and antagonists for human protease activated receptor 2. J Med Chem. 2010 Oct 28;53(20):7428-40.
• [5] Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110). Br J Pharmacol. 2012 Mar;165(5):1413-23.