Target Information

Target General Information

Target ID

T22658 (Former ID: TTDR00205)

Target Name

Interleukin-8 (IL8)

Synonyms

T-cell chemotactic factor; Protein 3-10C; Neutrophil-activating protein 1; NAP-1; Monocyte-derived neutrophil-activating peptide; Monocyte-derived neutrophil chemotactic factor; MONAP; MDNCF; IL8; IL-8; Granulocyte chemotactic protein 1; GCP-1; Emoctakin; Chemokine (C-X-C motif) ligand 8; C-X-C motif chemokine 8

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Gene Name

CXCL8

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Pain [ICD-11: MG30-MG3Z]

Function

IL-8 is a chemotactic factor that attracts neutrophils, basophils, and T-cells, but not monocytes. It is also involved in neutrophil activation. It is released from several cell types in response to an inflammatory stimulus. IL-8(6-77) has a 5-10-fold higher activity on neutrophil activation, IL-8(5-77) has increased activity on neutrophil activation and IL-8(7-77) has a higher affinity to receptors CXCR1 and CXCR2 as compared to IL-8(1-77), respectively.

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BioChemical Class

Cytokine: interleukin

UniProt ID

IL8_HUMAN

Sequence

MTSKLAVALLAAFLISAALCEGAVLPRSAKELRCQCIKTYSKPFHPKFIKELRVIESGPH
CANTEIIVKLSDGRELCLDPKENWVQRVVEKFLKRAENS

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3D Structure

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PDB

ADReCS ID

BADD_A00975 ; BADD_A05823 ; BADD_A05962

HIT2.0 ID

T54CIF

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)

[+] 3 Clinical Trial Drugs

ABX-IL8

Drug Info

Phase 2

Melanoma

[4]

BMS-986253

Drug Info

Phase 2

Coronavirus Disease 2019 (COVID-19)

[5]

MDX-018

Drug Info

Phase 1

Autoimmune diabetes

[6]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 8 Inhibitor drugs

Ibuprofen

Drug Info

[1]

BMS-986253

Drug Info

[8]

R-ketoprofen

Drug Info

[1]

2-(2-(2,5-dichlorophenylamino)phenyl)acetic acid

Drug Info

[1]

2-(2-(2-chlorophenoxy)phenyl)acetic acid

Drug Info

[1]

2-(2-(2-chlorophenylamino)phenyl)acetic acid

Drug Info

[1]

2-(2-(2-fluorophenoxy)phenyl)acetic acid

Drug Info

[1]

2-(2-(2-fluorophenylamino)phenyl)acetic acid

Drug Info

[1]

Modulator

[+] 1 Modulator drugs

MDX-018

Drug Info

[9]

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

There is no similarity protein (E value < 0.005) for this target

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
NF-kappa B signaling pathway	hsa04064	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Phospholipase D signaling pathway	hsa04072	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Cellular senescence	hsa04218	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Toll-like receptor signaling pathway	hsa04620	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
NOD-like receptor signaling pathway	hsa04621	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
RIG-I-like receptor signaling pathway	hsa04622	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
IL-17 signaling pathway	hsa04657	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	32	Degree centrality	3.44E-03	Betweenness centrality	1.65E-03
Closeness centrality	2.42E-01	Radiality	1.42E+01	Clustering coefficient	3.08E-01
Neighborhood connectivity	3.75E+01	Topological coefficient	7.47E-02	Eccentricity	11
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 Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 22 KEGG Pathways	+
1	Cytokine-cytokine receptor interaction
2	Chemokine signaling pathway
3	NF-kappa B signaling pathway
4	Toll-like receptor signaling pathway
5	NOD-like receptor signaling pathway
6	RIG-I-like receptor signaling pathway
7	Non-alcoholic fatty liver disease (NAFLD)
8	Epithelial cell signaling in Helicobacter pylori infection
9	Shigellosis
10	Salmonella infection
11	Pertussis
12	Legionellosis
13	Chagas disease (American trypanosomiasis)
14	Malaria
15	Amoebiasis
16	Hepatitis C
17	Hepatitis B
18	Influenza A
19	Pathways in cancer
20	Transcriptional misregulation in cancer
21	Bladder cancer
22	Rheumatoid arthritis
NetPath Pathway	[+] 10 NetPath Pathways	+
1	IL-7 Signaling Pathway
2	IL5 Signaling Pathway
3	IL1 Signaling Pathway
4	TSH Signaling Pathway
5	IL2 Signaling Pathway
6	IL3 Signaling Pathway
7	IL4 Signaling Pathway
8	TNFalpha Signaling Pathway
9	TSLP Signaling Pathway
10	TCR Signaling Pathway
Panther Pathway	[+] 3 Panther Pathways	+
1	Inflammation mediated by chemokine and cytokine signaling pathway
2	Interleukin signaling pathway
3	CCKR signaling map ST
PID Pathway	[+] 12 PID Pathways	+
1	LPA receptor mediated events
2	Calcineurin-regulated NFAT-dependent transcription in lymphocytes
3	Validated transcriptional targets of AP1 family members Fra1 and Fra2
4	Glucocorticoid receptor regulatory network
5	ATF-2 transcription factor network
6	IL8-mediated signaling events
7	AP-1 transcription factor network
8	IL8- and CXCR2-mediated signaling events
9	Regulation of nuclear beta catenin signaling and target gene transcription
10	Syndecan-2-mediated signaling events
11	Syndecan-3-mediated signaling events
12	IL8- and CXCR1-mediated signaling events
Reactome	[+] 5 Reactome Pathways	+
1	Senescence-Associated Secretory Phenotype (SASP)
2	Peptide ligand-binding receptors
3	Chemokine receptors bind chemokines
4	ATF4 activates genes
5	G alpha (i) signalling events
WikiPathways	[+] 14 WikiPathways	+
1	Toll-like receptor signaling pathway
2	SIDS Susceptibility Pathways
3	Senescence and Autophagy in Cancer
4	IL-3 Signaling Pathway
5	Bladder Cancer
6	Activation of Genes by ATF4
7	EBV LMP1 signaling
8	Spinal Cord Injury
9	Corticotropin-releasing hormone
10	Allograft Rejection
11	TSLP Signaling Pathway
12	GPCR ligand binding
13	GPCR downstream signaling
14	Regulation of toll-like receptor signaling pathway

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Structure-Activity Relationship of novel phenylacetic CXCR1 inhibitors. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4026-30.

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

ClinicalTrials.gov (NCT00035828) A Blinded Study Comparing the Safety and Efficacy of a Fully Human Anti-IL8 Monoclonal Antibody (ABX-IL8) to Placebo in Patients With Chronic Bronchitis and COPD. U.S. National Institutes of Health.

REF 5

ClinicalTrials.gov (NCT04347226) Anti-Interleukin-8 (Anti-IL-8) for Patients With COVID-19. U.S. National Institutes of Health.

REF 6

Clinical pipeline report, company report or official report of Genmab.

REF 7

Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol. 2002 Jul;161(1):125-34.

REF 8

Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J Immunother Cancer. 2019 Sep 5;7(1):240.

REF 9

Company report (Genmab)

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