Target Information
Target General Information | Top | |||||
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Target ID |
T63414
(Former ID: TTDC00218)
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Target Name |
P2X purinoceptor 7 (P2RX7)
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Synonyms |
Purinergic receptor 7; P2Z receptor; P2X7; Adenosine P2X7 receptor; ATP receptor
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Gene Name |
P2RX7
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Joint pain [ICD-11: ME82] | |||||
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.
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BioChemical Class |
ATP-gated P2X receptor cation channel
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UniProt ID | ||||||
Sequence |
MPACCSCSDVFQYETNKVTRIQSMNYGTIKWFFHVIIFSYVCFALVSDKLYQRKEPVISS
VHTKVKGIAEVKEEIVENGVKKLVHSVFDTADYTFPLQGNSFFVMTNFLKTEGQEQRLCP EYPTRRTLCSSDRGCKKGWMDPQSKGIQTGRCVVYEGNQKTCEVSAWCPIEAVEEAPRPA LLNSAENFTVLIKNNIDFPGHNYTTRNILPGLNITCTFHKTQNPQCPIFRLGDIFRETGD NFSDVAIQGGIMGIEIYWDCNLDRWFHHCRPKYSFRRLDDKTTNVSLYPGYNFRYAKYYK ENNVEKRTLIKVFGIRFDILVFGTGGKFDIIQLVVYIGSTLSYFGLAAVFIDFLIDTYSS NCCRSHIYPWCKCCQPCVVNEYYYRKKCESIVEPKPTLKYVSFVDESHIRMVNQQLLGRS LQDVKGQEVPRPAMDFTDLSRLPLALHDTPPIPGQPEEIQLLRKEATPRSRDSPVWCQCG SCLPSQLPESHRCLEELCCRKKPGACITTSELFRKLVLSRHVLQFLLLYQEPLLALDVDS TNSRLRHCAYRCYATWRFGSQDMADFAILPSCCRWRIRKEFPKSEGQYSGFKSPY Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T54B00 |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 10 Clinical Trial Drugs | + | ||||
1 | CE-224535 | Drug Info | Phase 2/3 | Arthralgia | [2] | |
2 | AZD9056 | Drug Info | Phase 2 | Chronic obstructive pulmonary disease | [3], [4] | |
3 | LY3857210 | Drug Info | Phase 2 | Pain | [5] | |
4 | BIL010t | Drug Info | Phase 1/2 | Solid tumour/cancer | [6] | |
5 | EVT 401 | Drug Info | Phase 1 | Rheumatoid arthritis | [7] | |
6 | GSK1482160 | Drug Info | Phase 1 | Pain | [8] | |
7 | JNJ-54175446 | Drug Info | Phase 1 | Major depressive disorder | [9] | |
8 | JNJ-55308942 | Drug Info | Phase 1 | Anhedonia | [6] | |
9 | SGM-1019 | Drug Info | Phase 1 | Inflammatory bowel disease | [10] | |
10 | JNJ-479655 | Drug Info | Clinical trial | Alzheimer disease | [11] | |
Mode of Action | [+] 4 Modes of Action | + | ||||
Antagonist | [+] 47 Antagonist drugs | + | ||||
1 | CE-224535 | Drug Info | [1] | |||
2 | AZD9056 | Drug Info | [12] | |||
3 | EVT 401 | Drug Info | [14] | |||
4 | GSK1482160 | Drug Info | [15] | |||
5 | JNJ-54175446 | Drug Info | [9] | |||
6 | JNJ-479655 | Drug Info | [16] | |||
7 | Aminobenzoxazole analog 1 | Drug Info | [17] | |||
8 | Benzamide derivative 12 | Drug Info | [17] | |||
9 | Benzamide derivative 13 | Drug Info | [17] | |||
10 | Bicyclic heteroaryl amide derivative 1 | Drug Info | [17] | |||
11 | Bicyclic heteroaryl amide derivative 2 | Drug Info | [17] | |||
12 | Bicyclic heteroaryl amide derivative 3 | Drug Info | [17] | |||
13 | Chlorobenzamide derivative 1 | Drug Info | [17] | |||
14 | Chlorobenzamide derivative 2 | Drug Info | [17] | |||
15 | Dihydroisoquinoline carboxamide analog 1 | Drug Info | [17] | |||
16 | Fluorophenyl-substituted heterocyclic amide analog 1 | Drug Info | [17] | |||
17 | Fused triazoloamino-phenyl analog 1 | Drug Info | [17] | |||
18 | Heterocyclic-fused piperazine derivative 1 | Drug Info | [17] | |||
19 | Imidazolidine derivative 1 | Drug Info | [17] | |||
20 | Indole carboxamide derivative 1 | Drug Info | [17] | |||
21 | Isoindole 1,3-dione analog 1 | Drug Info | [17] | |||
22 | Isothiazolidine derivative 1 | Drug Info | [17] | |||
23 | Piperazine derivative 6 | Drug Info | [17] | |||
24 | Piperidinone derivative 1 | Drug Info | [17] | |||
25 | PMID27724045-Compound-14 | Drug Info | [17] | |||
26 | PMID27724045-Compound-15 | Drug Info | [17] | |||
27 | PMID27724045-Compound-17 | Drug Info | [17] | |||
28 | PMID27724045-Compound-19 | Drug Info | [17] | |||
29 | PMID27724045-Compound-29 | Drug Info | [17] | |||
30 | PMID27724045-Compound-33 | Drug Info | [17] | |||
31 | Pyridazinone derivative 1 | Drug Info | [17] | |||
32 | Quinoline derivative 10 | Drug Info | [17] | |||
33 | Quinoline derivative 11 | Drug Info | [17] | |||
34 | Quinoline derivative 12 | Drug Info | [17] | |||
35 | Quinoline derivative 13 | Drug Info | [17] | |||
36 | Tetrazole derivative 1 | Drug Info | [17] | |||
37 | Thiazole derivative 5 | Drug Info | [17] | |||
38 | Thiazole-fused cycloalkyl carboxamide derivative 1 | Drug Info | [17] | |||
39 | Triazole derivative 2 | Drug Info | [17] | |||
40 | Triazolo-pyrazinone derivative 1 | Drug Info | [17] | |||
41 | A438079 | Drug Info | [19] | |||
42 | A804598 | Drug Info | [20] | |||
43 | A839977 | Drug Info | [21] | |||
44 | AFC-5128 | Drug Info | [20] | |||
45 | AZ-11657312 | Drug Info | [20] | |||
46 | AZ11657312 (salt free) | Drug Info | [20] | |||
47 | decavanadate | Drug Info | [24] | |||
Inhibitor | [+] 7 Inhibitor drugs | + | ||||
1 | LY3857210 | Drug Info | [13] | |||
2 | JNJ-55308942 | Drug Info | [6] | |||
3 | A-740003 | Drug Info | [18] | |||
4 | ISOPPADS | Drug Info | [25] | |||
5 | KN-62 | Drug Info | [26] | |||
6 | STYLISSADINE A | Drug Info | [18] | |||
7 | STYLISSADINE B | Drug Info | [18] | |||
Modulator | [+] 1 Modulator drugs | + | ||||
1 | SGM-1019 | Drug Info | [10] | |||
Modulator (allosteric modulator) | [+] 2 Modulator (allosteric modulator) drugs | + | ||||
1 | AZ11645373 | Drug Info | [22] | |||
2 | chelerythrine | Drug Info | [23] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Calcium signaling pathway | hsa04020 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
NOD-like receptor signaling pathway | hsa04621 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy |
Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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Closeness centrality | 1.43E-04 | Radiality | 5.80E-03 | Clustering coefficient | 0.00E+00 |
Neighborhood connectivity | 2.00E+00 | Topological coefficient | 1.00E+00 | Eccentricity | 2 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
1 | Calcium signaling pathway | |||||
2 | Neuroactive ligand-receptor interaction | |||||
Reactome | [+] 1 Reactome Pathways | + | ||||
1 | The NLRP3 inflammasome | |||||
WikiPathways | [+] 1 WikiPathways | + | ||||
1 | Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 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. | |||||
REF 2 | ClinicalTrials.gov (NCT00628095) Study of CE-224,535 A Twice Daily Pill To Control Rheumatoid Arthritis In Patients Who Have Not Totally Improved With Methotrexate. U.S. National Institutes of Health. | |||||
REF 3 | 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. (Ligand id: 7826). | |||||
REF 4 | ClinicalTrials.gov (NCT00520572) A 6-month Randomised, Double-blind, Open Arm Comparator, Phase IIb, With AZD9056, in Patients With Rheumatoid Arthritis (RA). U.S. National Institutes of Health. | |||||
REF 5 | ClinicalTrials.gov (NCT05630196) Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3857210 for the Treatment of Chronic Low Back Pain. U.S.National Institutes of Health. | |||||
REF 6 | Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357. | |||||
REF 7 | Clinical pipeline report, company report or official report of Evotec. | |||||
REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029786) | |||||
REF 9 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 10 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 11 | The role of the innate immune system in psychiatric disorders. Mol Cell Neurosci. 2013 Mar;53:52-62. | |||||
REF 12 | Clinical pipeline report, company report or official report of AstraZeneca (2009). | |||||
REF 13 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2023. Adis Insight | |||||
REF 14 | Molecular and functional properties of P2X receptors ecent progress and persisting challenges. Purinergic Signal. 2012 September; 8(3): 375-417. | |||||
REF 15 | Clinical pipeline report, company report or official report of GlaxoSmithKline (2009). | |||||
REF 16 | Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567. Br J Pharmacol. 2013 Oct;170(3):624-40. | |||||
REF 17 | P2X7 receptor antagonists: a patent review (2010-2015).Expert Opin Ther Pat. 2017 Mar;27(3):257-267. | |||||
REF 18 | Purinergic P2X(7) receptor antagonists: Chemistry and fundamentals of biological screening. Bioorg Med Chem. 2009 Jul 15;17(14):4861-5. | |||||
REF 19 | 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. | |||||
REF 20 | 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). | |||||
REF 21 | 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. | |||||
REF 22 | Mechanism of action of species-selective P2X(7) receptor antagonists. Br J Pharmacol. 2009 Apr;156(8):1312-25. | |||||
REF 23 | Chelerythrine and other benzophenanthridine alkaloids block the human P2X7 receptor. Br J Pharmacol. 2004 Jul;142(6):1015-9. | |||||
REF 24 | 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. | |||||
REF 25 | 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. | |||||
REF 26 | Synthesis and structure-activity relationships of pyrazolodiazepine derivatives as human P2X7 receptor antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6053-8. |
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