Target Information

Target General Information

Target ID

T46937 (Former ID: TTDS00113)

Target Name

P2Y purinoceptor 12 (P2RY12)

Synonyms

SP1999; P2Y12 platelet ADP receptor; P2Y12; P2Y(cyc); P2Y(ADP)P2Y purinoceptor 12; P2Y(ADP); P2Y(AC); P2T(AC); P2RY12; Nucleotide P2Y(12) receptor; Adenosine P2Y12 receptor; ADPG-R; ADP-glucose receptor

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Gene Name

P2RY12

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Myocardial infarction [ICD-11: BA41-BA43]

Thrombosis [ICD-11: DB61-GB90]

Function

Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Required for normal platelet aggregation and blood coagulation.

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BioChemical Class

GPCR rhodopsin

UniProt ID

P2Y12_HUMAN

Sequence

MQAVDNLTSAPGNTSLCTRDYKITQVLFPLLYTVLFFVGLITNGLAMRIFFQIRSKSNFI
IFLKNTVISDLLMILTFPFKILSDAKLGTGPLRTFVCQVTSVIFYFTMYISISFLGLITI
DRYQKTTRPFKTSNPKNLLGAKILSVVIWAFMFLLSLPNMILTNRQPRDKNVKKCSFLKS
EFGLVWHEIVNYICQVIFWINFLIVIVCYTLITKELYRSYVRTRGVGKVPRKKVNVKVFI
IIAVFFICFVPFHFARIPYTLSQTRDVFDCTAENTLFYVKESTLWLTSLNACLDPFIYFF
LCKSFRNSLISMLKCPNSATSLSQDNRKKEQDGGDPNEETPM

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3D Structure

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AlphaFold

HIT2.0 ID

T82RFG

Drugs and Modes of Action

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Approved Drug(s)

[+] 4 Approved Drugs

Brilinta

Drug Info

Approved

Thrombosis

[2], [3]

Cangrelor

Drug Info

Approved

Thrombosis

[4], [5]

Clopidogrel

Drug Info

Approved

Thrombosis

[6], [7], [8]

Prasugrel

Drug Info

Approved

Acute coronary syndrome

[9], [10]

Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

INS-50589

Drug Info

Phase 2

Cardiovascular disease

[11], [12]

ARL-67085

Drug Info

Phase 1

Thrombosis

[13], [14]

Elinogrel

Drug Info

Phase 1

Myocardial infarction

[15]

Mode of Action

[+] 4 Modes of Action

Antagonist

[+] 16 Antagonist drugs

Brilinta

Drug Info

[8], [16]

Cangrelor

Drug Info

[8]

Clopidogrel

Drug Info

[1], [8]

Elinogrel

Drug Info

[18]

2MeSAMP

Drug Info

[19]

ARL66096

Drug Info

[20]

BX 048

Drug Info

[21]

BX 667

Drug Info

[21]

INS49266

Drug Info

[22]

pCMPS

Drug Info

[1]

PMID22984835C20o

Drug Info

[23]

PMID22984835C4

Drug Info

[23]

PMID23083103C4

Drug Info

[24]

PRT-060096

Drug Info

[8]

R-138727

Drug Info

[26]

[3H]PSB-0413

Drug Info

[27]

Inhibitor

[+] 3 Inhibitor drugs

Prasugrel

Drug Info

[10]

PSB-0702

Drug Info

[25]

PSB-0739

Drug Info

[25]

Modulator

[+] 1 Modulator drugs

INS-50589

Drug Info

[17]

Agonist

[+] 3 Agonist drugs

ARL-67085

Drug Info

[14]

2MeSADP

Drug Info

[1], [19]

adenosine diphosphate

Drug Info

[1]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
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). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation

Different Human System Profiles of Target

Top

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).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 14J1 (OR14J1)	PF13853	25.309 (82/324)	1.26E-04


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.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Platelet activation	hsa04611	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Platelet activation

Reactome

[+] 2 Reactome Pathways

P2Y receptors

G alpha (i) signalling events

WikiPathways

[+] 4 WikiPathways

GPCRs, Class A Rhodopsin-like

Signal amplification

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med. 2003 May;3(2):113-22.

REF 2

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: 1765).

REF 3

2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.

REF 4

REF 5

ClinicalTrials.gov (NCT00385138) Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition.. U.S. National Institutes of Health.

REF 6

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029432)

REF 8

REF 9

REF 10

Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.

REF 11

REF 12

ClinicalTrials.gov (NCT00316212) Study of INS50589 Intravenous Infusion in Subjects Undergoing Coronary Artery Bypass Grafting (CABG) Involving Cardiopulmonary Bypass. U.S. National Institutes of Health.

REF 13

REF 14

Pharmacological characterization of the human P2Y11 receptor. Br J Pharmacol. 1999 Nov;128(6):1199-206.

REF 15

ClinicalTrials.gov (NCT00984113) Pharmacokinetics of Elinogrel in Healthy Volunteers and Patients With Mild, Moderate, and Severe Renal Impairment. U.S. National Institutes of Health.

REF 16

Clinical pipeline report, company report or official report of AstraZeneca (2009).

REF 17

Rapid and reversible modulation of platelet function in man by a novel P2Y(12) ADP-receptor antagonist, INS50589. Platelets. 2007 Aug;18(5):346-56.

REF 18

Elinogrel, a reversible P2Y12 receptor antagonist for the treatment of acute coronary syndrome and prevention of secondary thrombotic events. Curr Opin Investig Drugs. 2010 Mar;11(3):340-8.

REF 19

Molecular cloning of the platelet P2T(AC) ADP receptor: pharmacological comparison with another ADP receptor, the P2Y(1) receptor. Mol Pharmacol. 2001 Sep;60(3):432-9.

REF 20

FPL 66096: a novel, highly potent and selective antagonist at human platelet P2T-purinoceptors. Br J Pharmacol. 1994 Nov;113(3):1057-63.

REF 21

Novel P2Y12 adenosine diphosphate receptor antagonists for inhibition of platelet aggregation (II): pharmacodynamic and pharmacokinetic characterization. Thromb Res. 2008;122(4):533-40.

REF 22

Lipophilic modifications to dinucleoside polyphosphates and nucleotides that confer antagonist properties at the platelet P2Y12 receptor. J Med Chem. 2008 Feb 28;51(4):1007-25.

REF 23

Identification of high-affinity P2Y antagonists based on a phenylpyrazole glutamic acid piperazine backbone. J Med Chem. 2012 Oct 25;55(20):8615-29.

REF 24

Modified diadenosine tetraphosphates with dual specificity for P2Y1 and P2Y12 are potent antagonists of ADP-induced platelet activation. J Thromb Haemost. 2012 Dec;10(12):2573-80.

REF 25

High-affinity, non-nucleotide-derived competitive antagonists of platelet P2Y12 receptors. J Med Chem. 2009 Jun 25;52(12):3784-93.

REF 26

Stereoselective inhibition of human platelet aggregation by R-138727, the active metabolite of CS-747 (prasugrel, LY640315), a novel P2Y12 receptor inhibitor. Thromb Haemost. 2005 Sep;94(3):593-8.

REF 27

Synthesis and preliminary evaluation of [3H]PSB-0413, a selective antagonist radioligand for platelet P2Y12 receptors. Bioorg Med Chem Lett. 2005 Dec 15;15(24):5450-2.

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