Target Information
| Target General Information | Top | |||||
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| Target ID |
T03346
(Former ID: TTDC00081)
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| Target Name |
Interleukin 4 receptor alpha (IL4R)
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| Synonyms |
Interleukin-4 receptor subunit alpha; IL4RA; IL-4RA; IL-4R-alpha; IL-4R subunit alpha; IL-4 receptor subunit alpha; CD124 antigen; CD124; 582J2.1
Click to Show/Hide
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| Gene Name |
IL4R
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Atopic eczema [ICD-11: EA80] | |||||
| Function |
Couples to the JAK1/2/3-STAT6 pathway. The IL4 response is involved in promoting Th2 differentiation. The IL4/IL13 responses are involved in regulating IgE production and, chemokine and mucus production at sites of allergic inflammation. In certain cell types, can signal through activation of insulin receptor substrates, IRS1/IRS2. Receptor for both interleukin 4 and interleukin 13.
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| BioChemical Class |
Cytokine receptor
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| UniProt ID | ||||||
| Sequence |
MGWLCSGLLFPVSCLVLLQVASSGNMKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRL
LYQLVFLLSEAHTCIPENNGGAGCVCHLLMDDVVSADNYTLDLWAGQQLLWKGSFKPSEH VKPRAPGNLTVHTNVSDTLLLTWSNPYPPDNYLYNHLTYAVNIWSENDPADFRIYNVTYL EPSLRIAASTLKSGISYRARVRAWAQCYNTTWSEWSPSTKWHNSYREPFEQHLLLGVSVS CIVILAVCLLCYVSITKIKKEWWDQIPNPARSRLVAIIIQDAQGSQWEKRSRGQEPAKCP HWKNCLTKLLPCFLEHNMKRDEDPHKAAKEMPFQGSGKSAWCPVEISKTVLWPESISVVR CVELFEAPVECEEEEEVEEEKGSFCASPESSRDDFQEGREGIVARLTESLFLDLLGEENG GFCQQDMGESCLLPPSGSTSAHMPWDEFPSAGPKEAPPWGKEQPLHLEPSPPASPTQSPD NLTCTETPLVIAGNPAYRSFSNSLSQSPCPRELGPDPLLARHLEEVEPEMPCVPQLSEPT TVPQPEPETWEQILRRNVLQHGAAAAPVSAPTSGYQEFVHAVEQGGTQASAVVGLGPPGE AGYKAFSSLLASSAVSPEKCGFGASSGEEGYKPFQDLIPGCPGDPAPVPVPLFTFGLDRE PPRSPQSSHLPSSSPEHLGLEPGEKVEDMPKPPLPQEQATDPLVDSLGSGIVYSALTCHL CGHLKQCHGQEDGGQTPVMASPCCGCCCGDRSSPPTTPLRAPDPSPGGVPLEASLCPASL APSGISEKSKSSSSFHPAPGNAQSSSQTPKIVNFVSVGPTYMRVS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Dupilumab | Drug Info | Approved | Atopic dermatitis | [2] | |
| Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
| 1 | SAR231893 | Drug Info | Phase 3 | Atopic dermatitis | [4] | |
| 2 | Aerovant | Drug Info | Phase 2a | Asthma | [5] | |
| 3 | Altrakincept | Drug Info | Phase 2 | Asthma | [7] | |
| 4 | PRX-321 | Drug Info | Phase 2 | Solid tumour/cancer | [8] | |
| 5 | SAR-156597 | Drug Info | Phase 2 | Pulmonary fibrosis | [9] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | AMG 317 | Drug Info | Discontinued in Phase 1 | Asthma | [10] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | SAR231893 | Drug Info | [1], [11] | |||
| 2 | Altrakincept | Drug Info | [13] | |||
| Antagonist | [+] 2 Antagonist drugs | + | ||||
| 1 | Aerovant | Drug Info | [12] | |||
| 2 | AMG 317 | Drug Info | [16], [17] | |||
| Agonist | [+] 1 Agonist drugs | + | ||||
| 1 | PRX-321 | Drug Info | [14] | |||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | PRS-060 | Drug Info | [15] | |||
| 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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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
|---|---|---|---|
| Interleukin 3 receptor (CSF2RB) | 24.031 (62/258) | 4.06E-13 | |
| Interleukin 21 receptor (IL21R) | 24.706 (63/255) | 9.43E-06 | |
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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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| Cytokine-cytokine receptor interaction | hsa04060 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| PI3K-Akt signaling pathway | hsa04151 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| JAK-STAT signaling pathway | hsa04630 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Hematopoietic cell lineage | hsa04640 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Th1 and Th2 cell differentiation | hsa04658 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Th17 cell differentiation | hsa04659 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 12 | Degree centrality | 1.29E-03 | Betweenness centrality | 1.82E-05 |
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| Closeness centrality | 2.21E-01 | Radiality | 1.39E+01 | Clustering coefficient | 4.09E-01 |
| Neighborhood connectivity | 3.54E+01 | Topological coefficient | 1.62E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Regulators | Top | |||||
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| Target-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
|---|---|---|---|---|---|---|
| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
| 1 | Cytokine-cytokine receptor interaction | |||||
| 2 | PI3K-Akt signaling pathway | |||||
| 3 | Jak-STAT signaling pathway | |||||
| 4 | Hematopoietic cell lineage | |||||
| 5 | Inflammatory bowel disease (IBD) | |||||
| NetPath Pathway | [+] 3 NetPath Pathways | + | ||||
| 1 | IL2 Signaling Pathway | |||||
| 2 | IL4 Signaling Pathway | |||||
| 3 | EGFR1 Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Interleukin signaling pathway | |||||
| PID Pathway | [+] 2 PID Pathways | + | ||||
| 1 | p73 transcription factor network | |||||
| 2 | IL4-mediated signaling events | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Inflammatory Response Pathway | |||||
| 2 | IL-4 Signaling Pathway | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26):2455-66. | |||||
| REF 2 | 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85. | |||||
| REF 3 | ClinicalTrials.gov (NCT05614817) A Randomized, Double-blind, Placebo-controlled Phase 3 Trial to Evaluate the Efficacy and Safety of CBP-201 Monotherapy in Patients With Moderate-To-Severe Atopic Dermatitis Who Are Candidates for Systemic Therapy. U.S.National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT02134028) Long-Term Safety Evaluation of Dupilumab in Patients With Asthma. U.S. National Institutes of Health. | |||||
| REF 5 | Emerging drugs for asthma. Expert Opin Emerg Drugs. 2008 Dec;13(4):643-53. | |||||
| REF 6 | ClinicalTrials.gov (NCT04643158) A Two-part Phase IIa Randomised, Double-blind, Placebo-controlled, Dose-ranging, Multi-centre Study to Assess Efficacy and Safety of Inhaled AZD1402 Administered as a Dry Powder for Four Weeks in Adults With Asthma on Medium-to-High Dose Inhaled Corticosteroids. U.S.National Institutes of Health. | |||||
| REF 7 | Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med. 1999 Dec;160(6):1816-23. | |||||
| REF 8 | ClinicalTrials.gov (NCT00797940) Convection Enhanced Localized Administration of PRX321 With Real-time Imaging for Therapy of Recurrent Glioblastoma (CLARITY-1). U.S. National Institutes of Health. | |||||
| REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034106) | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017312) | |||||
| REF 11 | ClinicalTrials.gov (NCT02277769) Study of Dupilumab (REGN668/SAR231893) Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis. U.S. National Institutes of Health. | |||||
| REF 12 | Aerovance starts trial of Aerovant for uncontrolled asthma. Aerovance. March 3, 2009. | |||||
| REF 13 | The potential of biologics for the treatment of asthma. Nat Rev Drug Discov. 2012 Dec;11(12):958-72. | |||||
| REF 14 | Convection-enhanced drug delivery of interleukin-4 Pseudomonas exotoxin (PRX321): increased distribution and magnetic resonance monitoring. J Pharmacol Exp Ther. 2009 Aug;330(2):520-5. | |||||
| REF 15 | 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: 1697). | |||||
| REF 16 | Clinical pipeline report, company report or official report of Amgen (2009). | |||||
| REF 17 | Randomized, double-blind, placebo-controlled trial of the oral interleukin-12/23 inhibitor apilimod mesylate for treatment of active Crohn's disease. Inflamm Bowel Dis. 2010 Jul;16(7):1209-18. | |||||
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