Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT473XN)

• DTT Name: P2X purinoceptor 7 (P2RX7)
• Synonyms: Purinergic receptor 7; P2Z receptor; P2X7; Adenosine P2X7 receptor; ATP receptor
• Gene Name: P2RX7
• DTT Type: Clinical trial target; [1]
• Related Disease: Joint pain [ICD-11: ME82]
• BioChemical Class: ATP-gated P2X receptor cation channel
• UniProt ID: P2RX7_HUMAN
• TTD ID: T63414
• Sequence:
  MPACCSCSDVFQYETNKVTRIQSMNYGTIKWFFHVIIFSYVCFALVSDKLYQRKEPVISS
  VHTKVKGIAEVKEEIVENGVKKLVHSVFDTADYTFPLQGNSFFVMTNFLKTEGQEQRLCP
  EYPTRRTLCSSDRGCKKGWMDPQSKGIQTGRCVVYEGNQKTCEVSAWCPIEAVEEAPRPA
  LLNSAENFTVLIKNNIDFPGHNYTTRNILPGLNITCTFHKTQNPQCPIFRLGDIFRETGD
  NFSDVAIQGGIMGIEIYWDCNLDRWFHHCRPKYSFRRLDDKTTNVSLYPGYNFRYAKYYK
  ENNVEKRTLIKVFGIRFDILVFGTGGKFDIIQLVVYIGSTLSYFGLAAVFIDFLIDTYSS
  NCCRSHIYPWCKCCQPCVVNEYYYRKKCESIVEPKPTLKYVSFVDESHIRMVNQQLLGRS
  LQDVKGQEVPRPAMDFTDLSRLPLALHDTPPIPGQPEEIQLLRKEATPRSRDSPVWCQCG
  SCLPSQLPESHRCLEELCCRKKPGACITTSELFRKLVLSRHVLQFLLLYQEPLLALDVDS
  TNSRLRHCAYRCYATWRFGSQDMADFAILPSCCRWRIRKEFPKSEGQYSGFKSPY
• Function: Responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Could function in both fast synaptic transmission and the ATP-mediated lysis of antigen-presenting cells. In the absence of its natural ligand, ATP, functions as a scavenger receptor in the recognition and engulfment of apoptotic cells. Receptor for ATP that acts as a ligand-gated ion channel.
• Reactome Pathway: The NLRP3 inflammasome (R-HSA-844456)

Molecular Interaction Atlas (MIA) of This DTT

9 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CE-224535	DMFCLT6	Arthralgia	ME82	Phase 2/3	[1]
AZD9056	DMJGYPK	Chronic obstructive pulmonary disease	CA22	Phase 2	[2]
BIL010t	DMV1EA9	Alzheimer disease	8A20	Phase 1/2	[3]
EVT 401	DMOG8IE	Rheumatoid arthritis	FA20	Phase 1	[4]
GSK1482160	DMWDQOV	Pain	MG30-MG3Z	Phase 1	[5]
JNJ-54175446	DMQ5ZVK	Major depressive disorder	6A70.3	Phase 1	[6]
JNJ-55308942	DM0QZJX	Anhedonia	MB24.2	Phase 1	[3]
SGM-1019	DMDAHEL	Inflammatory bowel disease	DD72	Phase 1	[7]
JNJ-479655	DMDU6GN	Alzheimer disease	8A20	Clinical trial	[8]

34 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminobenzoxazole analog 1	DM1RQIU	N. A.	N. A.	Patented	[9]
Benzamide derivative 12	DMS527F	N. A.	N. A.	Patented	[9]
Benzamide derivative 13	DMYSH9J	N. A.	N. A.	Patented	[9]
Bicyclic heteroaryl amide derivative 1	DMOFI09	N. A.	N. A.	Patented	[9]
Bicyclic heteroaryl amide derivative 2	DM69HL5	N. A.	N. A.	Patented	[9]
Bicyclic heteroaryl amide derivative 3	DM0OYCX	N. A.	N. A.	Patented	[9]
Chlorobenzamide derivative 1	DMR39ZY	N. A.	N. A.	Patented	[9]
Chlorobenzamide derivative 2	DMKS7O3	N. A.	N. A.	Patented	[9]
Dihydroisoquinoline carboxamide analog 1	DM5UPGZ	N. A.	N. A.	Patented	[9]
Fluorophenyl-substituted heterocyclic amide analog 1	DMTS8O9	N. A.	N. A.	Patented	[9]
Fused triazoloamino-phenyl analog 1	DM4Z72S	N. A.	N. A.	Patented	[9]
Heterocyclic-fused piperazine derivative 1	DMEGK3Q	N. A.	N. A.	Patented	[9]
Imidazolidine derivative 1	DMECJDM	N. A.	N. A.	Patented	[9]
Indole carboxamide derivative 1	DMLHGC9	N. A.	N. A.	Patented	[9]
Isoindole 1,3-dione analog 1	DMWTU8X	N. A.	N. A.	Patented	[9]
Isothiazolidine derivative 1	DMLSUH3	N. A.	N. A.	Patented	[9]
Piperazine derivative 6	DMDL3A5	N. A.	N. A.	Patented	[9]
Piperidinone derivative 1	DMAM50X	N. A.	N. A.	Patented	[9]
PMID27724045-Compound-14	DMTJ0LB	N. A.	N. A.	Patented	[9]
PMID27724045-Compound-15	DMVN5BD	N. A.	N. A.	Patented	[9]
PMID27724045-Compound-17	DM4W72V	N. A.	N. A.	Patented	[9]
PMID27724045-Compound-19	DMVDBHT	N. A.	N. A.	Patented	[9]
PMID27724045-Compound-29	DMKTQX8	N. A.	N. A.	Patented	[9]
PMID27724045-Compound-33	DMOS7ZP	N. A.	N. A.	Patented	[9]
Pyridazinone derivative 1	DMF7MEB	N. A.	N. A.	Patented	[9]
Quinoline derivative 10	DM6GSCV	N. A.	N. A.	Patented	[9]
Quinoline derivative 11	DMH02JL	N. A.	N. A.	Patented	[9]
Quinoline derivative 12	DM9FXE7	N. A.	N. A.	Patented	[9]
Quinoline derivative 13	DMAH4P8	N. A.	N. A.	Patented	[9]
Tetrazole derivative 1	DM1AGSD	N. A.	N. A.	Patented	[9]
Thiazole derivative 5	DMESAUL	N. A.	N. A.	Patented	[9]
Thiazole-fused cycloalkyl carboxamide derivative 1	DMCPV0D	N. A.	N. A.	Patented	[9]
Triazole derivative 2	DM7KNXH	N. A.	N. A.	Patented	[9]
Triazolo-pyrazinone derivative 1	DM1KHGY	N. A.	N. A.	Patented	[9]

14 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
A-740003	DMI7J1L	Discovery agent	N.A.	Investigative	[10]
A438079	DMUBM8X	Discovery agent	N.A.	Investigative	[11]
A804598	DMLC7HE	N. A.	N. A.	Investigative	[12]
A839977	DMPXKOE	Discovery agent	N.A.	Investigative	[13]
AFC-5128	DM65TUP	Autoimmune diabetes	5A10	Investigative	[12]
AZ-11657312	DMRUA0Y	Inflammation	1A00-CA43.1	Investigative	[12]
AZ11645373	DMDRXCP	Discovery agent	N.A.	Investigative	[14]
AZ11657312 (salt free)	DMVX8LO	Discovery agent	N.A.	Investigative	[12]
Chelerythrine	DMCP1G9	Discovery agent	N.A.	Investigative	[15]
decavanadate	DMLT1N3	Discovery agent	N.A.	Investigative	[16]
ISOPPADS	DMWI0M8	Discovery agent	N.A.	Investigative	[17]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[18]
STYLISSADINE A	DMO9VWJ	Discovery agent	N.A.	Investigative	[10]
STYLISSADINE B	DMNAYEP	Discovery agent	N.A.	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	1.11E-06	0.37	0.49
Rheumatoid arthritis	FA20	Synovial tissue	1.71E-02	1.08	1.25
Chronic obstructive pulmonary disease	CA23	Lung tissue	3.17E-01	-0.1	-0.22
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	5.97E-02	0.16	0.37

References

• [1] Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J Rheumatol. 2012 Apr;39(4):720-7.
• [2] Clinical pipeline report, company report or official report of AstraZeneca (2009).
• [3] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [4] Molecular and functional properties of P2X receptors ecent progress and persisting challenges. Purinergic Signal. 2012 September; 8(3): 375-417.
• [5] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567. Br J Pharmacol. 2013 Oct;170(3):624-40.
• [9] P2X7 receptor antagonists: a patent review (2010-2015).Expert Opin Ther Pat. 2017 Mar;27(3):257-267.
• [10] Purinergic P2X(7) receptor antagonists: Chemistry and fundamentals of biological screening. Bioorg Med Chem. 2009 Jul 15;17(14):4861-5.
• [11] Discovery of P2X7 receptor-selective antagonists offers new insights into P2X7 receptor function and indicates a role in chronic pain states. Br J Pharmacol. 2007 Jul;151(5):571-9.
• [12] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 484).
• [13] The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1alphabeta knockout mice. Behav Brain Res. 2009 Dec 1;204(1):77-81.
• [14] Mechanism of action of species-selective P2X(7) receptor antagonists. Br J Pharmacol. 2009 Apr;156(8):1312-25.
• [15] Chelerythrine and other benzophenanthridine alkaloids block the human P2X7 receptor. Br J Pharmacol. 2004 Jul;142(6):1015-9.
• [16] Decavanadate, a P2X receptor antagonist, and its use to study ligand interactions with P2X7 receptors. Eur J Pharmacol. 2006 Mar 18;534(1-3):19-29.
• [17] Structure-activity relationship studies of spinorphin as a potent and selective human P2X(3) receptor antagonist. J Med Chem. 2007 Sep 6;50(18):4543-7.
• [18] Synthesis and structure-activity relationships of pyrazolodiazepine derivatives as human P2X7 receptor antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6053-8.