Target Information

Target General Information

Target ID

T00884 (Former ID: TTDC00190)

Target Name

C-X-C chemokine receptor type 1 (CXCR1)

Synonyms

Interleukin-8 receptor A; IL8RA; IL-8R A; IL-8 receptor type 1; High affinity interleukin-8 receptor A; CXCR-1; CXC-R1; CMKAR1; CDw128a; CD181

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Gene Name

CXCR1

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Pain [ICD-11: MG30-MG3Z]

Function

Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activate a phosphatidylinositol-calcium second messenger system. This receptor binds to IL-8 with a high affinity and to MGSA (GRO) with a low affinity. Receptor to interleukin-8, which is a powerful neutrophils chemotactic factor.

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BioChemical Class

GPCR rhodopsin

UniProt ID

CXCR1_HUMAN

Sequence

MSNITDPQMWDFDDLNFTGMPPADEDYSPCMLETETLNKYVVIIAYALVFLLSLLGNSLV
MLVILYSRVGRSVTDVYLLNLALADLLFALTLPIWAASKVNGWIFGTFLCKVVSLLKEVN
FYSGILLLACISVDRYLAIVHATRTLTQKRHLVKFVCLGCWGLSMNLSLPFFLFRQAYHP
NNSSPVCYEVLGNDTAKWRMVLRILPHTFGFIVPLFVMLFCYGFTLRTLFKAHMGQKHRA
MRVIFAVVLIFLLCWLPYNLVLLADTLMRTQVIQESCERRNNIGRALDATEILGFLHSCL
NPIIYAFIGQNFRHGFLKILAMHGLVSKEFLARHRVTSYTSSSVNVSSNL

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3D Structure

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PDB

HIT2.0 ID

T70DWW

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Ibuprofen

Drug Info

Approved

Pain

[2], [3]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

Reparixin

Drug Info

Phase 3

Pancreatic islet transplantation failure

[4]

SCH-527123

Drug Info

Phase 2

Inflammatory bowel disease

[5]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

INDOPROFEN

Drug Info

Withdrawn from market

Gout

[7]

Mode of Action

[+] 4 Modes of Action

Inhibitor

[+] 11 Inhibitor drugs

Ibuprofen

Drug Info

[1]

INDOPROFEN

Drug Info

[1]

(R)-2-(4-Isobutyl-phenyl)-N-methoxy-propionamide

Drug Info

[1]

(R)-2-(4-Isobutyl-phenyl)-propionamide

Drug Info

[1]

(R)-N-Hydroxy-2-(4-isobutyl-phenyl)-propionamide

Drug Info

[1]

1-(2-Bromo-phenyl)-3-(2,4-dihydroxy-phenyl)-urea

Drug Info

[10]

2-(3-Isobutyl-phenyl)-propionic acid

Drug Info

[1]

2-(3-Isopropyl-phenyl)-propionic acid

Drug Info

[1]

2-[3-(1-Hydroxy-propyl)-phenyl]-propionic acid

Drug Info

[1]

2-[3-(1-Phenyl-ethyl)-phenyl]-propionic acid

Drug Info

[1]

2-[3-(2-Methyl-butyl)-phenyl]-propionic acid

Drug Info

[1]

Modulator

[+] 1 Modulator drugs

Reparixin

Drug Info

[1], [8]

Antagonist

[+] 1 Antagonist drugs

SCH-527123

Drug Info

[9]

Agonist

[+] 1 Agonist drugs

Il-8((3-73))K11R

Drug Info

[11]

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 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 2T4 (OR2T4)	PF13853	24.419 (42/172)	3.00E-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
Phospholipase D signaling pathway	hsa04072	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Endocytosis	hsa04144	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy

Degree	7	Degree centrality	7.52E-04	Betweenness centrality	8.44E-05
Closeness centrality	1.98E-01	Radiality	1.34E+01	Clustering coefficient	4.76E-02
Neighborhood connectivity	1.26E+01	Topological coefficient	2.47E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

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 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

[+] 4 KEGG Pathways

Cytokine-cytokine receptor interaction

Chemokine signaling pathway

Endocytosis

Epithelial cell signaling in Helicobacter pylori infection

NetPath Pathway

[+] 1 NetPath Pathways

IL2 Signaling Pathway

Panther Pathway

[+] 2 Panther Pathways

Inflammation mediated by chemokine and cytokine signaling pathway

Interleukin signaling pathway

PID Pathway

[+] 1 PID Pathways

IL8- and CXCR1-mediated signaling events

Reactome

[+] 2 Reactome Pathways

Chemokine receptors bind chemokines

G alpha (i) signalling events

WikiPathways

[+] 6 WikiPathways

GPCRs, Class A Rhodopsin-like

Differentiation Pathway

Peptide GPCRs

GPCR ligand binding

GPCR downstream signaling

GPCRs, Other

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors. J Med Chem. 2005 Jun 30;48(13):4312-31.

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: 2713).

REF 3

New drugs in development for the treatment of endometriosis. Expert Opin Investig Drugs. 2008 Aug;17(8):1187-202.

REF 4

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

REF 5

Emerging drugs to treat Crohn's disease. Expert Opin Emerg Drugs. 2007 Mar;12(1):49-59.

REF 6

ClinicalTrials.gov (NCT03161431) SX-682 Treatment in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab. U.S. National Institutes of Health.

REF 7

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 8

Reparixin, an inhibitor of CXCR1 and CXCR2 receptor activation, attenuates blood pressure and hypertension-related mediators expression in spontane... Biol Pharm Bull. 2011;34(1):120-7.

REF 9

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

REF 10

Synthesis and structure-activity relationships of 3,5-diarylisoxazoles and 3,5-diaryl-1,2,4-oxadiazoles, novel classes of small molecule interleuki... Bioorg Med Chem Lett. 2004 Aug 16;14(16):4307-11.

REF 11

Il-8((3-73))K11R is a high affinity agonist of the neutrophil CXCR1 and CXCR2. Biochem Biophys Res Commun. 2001 Aug 24;286(3):595-600.

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