Target Information

Target General Information

Target ID

T97873 (Former ID: TTDNC00667)

Target Name

C-C chemokine receptor type 9 (CCR9)

Synonyms

Gprotein coupled receptor 28; GPR96; GPR28; GPR-9-6; G-protein coupled receptor 28; CDw199; CCR-9; CCCKR9; CC-CKR-9; CC chemokine receptor type 9; CC CKR9; C-C CKR-9

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Gene Name

CCR9

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Crohn disease [ICD-11: DD70]

Function

Subsequently transduces a signal by increasing the intracellular calcium ions level. Receptor for chemokine SCYA25/TECK.

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BioChemical Class

GPCR rhodopsin

UniProt ID

CCR9_HUMAN

Sequence

MTPTDFTSPIPNMADDYGSESTSSMEDYVNFNFTDFYCEKNNVRQFASHFLPPLYWLVFI
VGALGNSLVILVYWYCTRVKTMTDMFLLNLAIADLLFLVTLPFWAIAAADQWKFQTFMCK
VVNSMYKMNFYSCVLLIMCISVDRYIAIAQAMRAHTWREKRLLYSKMVCFTIWVLAAALC
IPEILYSQIKEESGIAICTMVYPSDESTKLKSAVLTLKVILGFFLPFVVMACCYTIIIHT
LIQAKKSSKHKALKVTITVLTVFVLSQFPYNCILLVQTIDAYAMFISNCAVSTNIDICFQ
VTQTIAFFHSCLNPVLYVFVGERFRRDLVKTLKNLGCISQAQWVSFTRREGSLKLSSMLL
ETTSGALSL

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3D Structure

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PDB

ADReCS ID

BADD_A06414 ; BADD_A08478

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 4 Clinical Trial Drugs

Vercirnon

Drug Info

Phase 3

Crohn disease

[2]

CCX-025

Drug Info

Phase 1

Crohn disease

[3]

CCX507

Drug Info

Phase 1

Ulcerative colitis

[4]

MLN-3126

Drug Info

Phase 1

Sjogren syndrome

[5]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 1 Modulator drugs

Vercirnon

Drug Info

[1]

Antagonist

[+] 3 Antagonist drugs

CCX-025

Drug Info

[1], [6]

CCX507

Drug Info

[4]

MLN-3126

Drug Info

[1], [6]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Vercirnon

Ligand Info

Structure Description

Crystal structure of the human CC chemokine receptor type 9 (CCR9) in complex with vercirnon

PDB:5LWE

Method

X-ray diffraction

Resolution

2.80 Å

Mutation

[7]

PDB Sequence

RQFASHFLPP

⁵³

LYWLVFIVGA

⁶³

LGNSLVILVY

⁷³

WYCARAKTAT

⁸³

DMFLLNLAIA

⁹³

DLLFLVTLPF

¹⁰³

WAIATFMCKV

¹²¹

VNSMYKMNFY

¹³¹

SCVLLIMCIC

¹⁴¹

VDRYIAIAQA

¹⁵¹

MRAHTWREKR

¹⁶¹

LLYSKMVCFT

¹⁷¹

IWVLAAALCI

¹⁸¹

PEILYCTTKL

²¹⁰

KSAVLALKVI

²²⁰

LGFFLPFVVM

²³⁰

ACCYTIIIHT

²⁴⁰

LIQAKKSSKH

²⁵⁰

KALKATITVL

²⁶⁰

TVFVLSQFPY

²⁷⁰

NCILLVQTID

²⁸⁰

AYAMFISNCA

²⁹⁰

VSTAIDICFQ

³⁰⁰

VTQAIAFFHS

³¹⁰

CLNPVLYVFV

³²⁰

GERFRRDLVK

³³⁰

TLKNLGAISQ

³⁴⁰

AAAHH

Residue

Distance (Å)

VAL69

3.377

VAL72

3.851

TYR73

3.813

CYS76

4.795

ARG78

3.333

LYS80

4.565

THR81

3.186

THR83

3.659

ASP84

3.113

LEU87

3.590

LEU88

4.359

ILE140

3.739

Residue

Distance (Å)

ARG144

3.408

ALA252

3.927

ALA255

3.562

THR256

3.532

VAL259

3.678

TYR317

3.594

VAL320

4.976

GLY321

3.031

GLU322

3.166

ARG323

2.744

PHE324

2.942

ASP327

3.530

Ligand Name: Cholesterol

Ligand Info

Structure Description

Crystal structure of the human CC chemokine receptor type 9 (CCR9) in complex with vercirnon

PDB:5LWE

Method

X-ray diffraction

Resolution

2.80 Å

Mutation

[7]

PDB Sequence

RQFASHFLPP

⁵³

LYWLVFIVGA

⁶³

LGNSLVILVY

⁷³

WYCARAKTAT

⁸³

DMFLLNLAIA

⁹³

DLLFLVTLPF

¹⁰³

WAIATFMCKV

¹²¹

VNSMYKMNFY

¹³¹

SCVLLIMCIC

¹⁴¹

VDRYIAIAQA

¹⁵¹

MRAHTWREKR

¹⁶¹

LLYSKMVCFT

¹⁷¹

IWVLAAALCI

¹⁸¹

PEILYCTTKL

²¹⁰

KSAVLALKVI

²²⁰

LGFFLPFVVM

²³⁰

ACCYTIIIHT

²⁴⁰

LIQAKKSSKH

²⁵⁰

KALKATITVL

²⁶⁰

TVFVLSQFPY

²⁷⁰

NCILLVQTID

²⁸⁰

AYAMFISNCA

²⁹⁰

VSTAIDICFQ

³⁰⁰

VTQAIAFFHS

³¹⁰

CLNPVLYVFV

³²⁰

GERFRRDLVK

³³⁰

TLKNLGAISQ

³⁴⁰

AAAHH

Residue

Distance (Å)

LYS254

4.329

THR258

4.126

VAL262

4.373

PHE308

3.546

LEU312

3.811

Residue

Distance (Å)

VAL315

4.645

LEU316

3.707

PHE319

4.061

VAL320

3.941

Click to View More Binding Site Information of This Target with Different Ligands

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 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 Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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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 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 Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 2T3 (OR2T3)	PF13853	21.612 (59/273)	5.78E-05
Olfactory receptor 13J1 (OR13J1)	PF13853	25.000 (35/140)	1.00E-03
Olfactory receptor 2T34 (OR2T34)	PF13853	22.143 (62/280)	2.00E-03

KEGG Pathway	Pathway ID	Affiliated Target
Cytokine-cytokine receptor interaction	hsa04060	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Viral protein interaction with cytokine and cytokine receptor	hsa04061	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Chemokine signaling pathway	hsa04062	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Intestinal immune network for IgA production	hsa04672	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.17E-01	Radiality	1.03E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	2.00E+00	Topological coefficient	1.00E+00	Eccentricity	16
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Cytokine-cytokine receptor interaction

Chemokine signaling pathway

Intestinal immune network for IgA production

Panther Pathway

[+] 1 Panther Pathways

Inflammation mediated by chemokine and cytokine signaling pathway

Reactome

[+] 2 Reactome Pathways

Chemokine receptors bind chemokines

G alpha (i) signalling events

WikiPathways

[+] 4 WikiPathways

GPCRs, Class A Rhodopsin-like

Peptide GPCRs

GPCR ligand binding

GPCR downstream signaling

References

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REF 1

GSK-1605786, a selective small-molecule antagonist of the CCR9 chemokine receptor for the treatment of Crohn's disease. IDrugs. 2010 Jul;13(7):472-81.

REF 2

ClinicalTrials.gov (NCT01536418) An Active Treatment Study to Induce Clinical Response and/or Remission With GSK1605786A in Subjects With Crohn's Disease. U.S. National Institutes of Health.

REF 3

Clinical pipeline report, company report or official report of ChemoCentryx Inc.

REF 4

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 5

ClinicalTrials.gov (NCT02209506) Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MLN3126 in Healthy Japanese and Non-Japanese Participants. U.S. National Institutes of Health.

REF 6

Targeting T-cell migration in inflammatory bowel disease. J Intern Med. 2012 Nov;272(5):411-29.

REF 7

Intracellular allosteric antagonism of the CCR9 receptor. Nature. 2016 Dec 15;540(7633):462-465.

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