Target Information
| Target General Information | Top | |||||
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| Target ID |
T06955
(Former ID: TTDC00226)
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| Target Name |
C-C chemokine receptor type 4 (CCR4)
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| Synonyms |
K5-5; CMKBR4; CD194; CCR-4; CC-CKR-4; CC chemokine receptor 4; C-CCKR-4; C-C CKR-4
Click to Show/Hide
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| Gene Name |
CCR4
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Mycosis fungoides [ICD-11: 2B01] | |||||
| 2 | Sezary syndrome [ICD-11: 2B02] | |||||
| Function |
The activity of this receptor is mediated by G(i) proteins which activate a phosphatidylinositol-calcium second messenger system. Can function as a chemoattractant homing receptor on circulating memory lymphocytes and as a coreceptor for some primary HIV-2 isolates. In the CNS, could mediate hippocampal-neuron survival. High affinity receptor for the C-C type chemokines CCL17/TARC, CCL22/MDC and CKLF isoform 1/CKLF1.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MNPTDIADTTLDESIYSNYYLYESIPKPCTKEGIKAFGELFLPPLYSLVFVFGLLGNSVV
VLVLFKYKRLRSMTDVYLLNLAISDLLFVFSLPFWGYYAADQWVFGLGLCKMISWMYLVG FYSGIFFVMLMSIDRYLAIVHAVFSLRARTLTYGVITSLATWSVAVFASLPGFLFSTCYT ERNHTYCKTKYSLNSTTWKVLSSLEINILGLVIPLGIMLFCYSMIIRTLQHCKNEKKNKA VKMIFAVVVLFLGFWTPYNIVLFLETLVELEVLQDCTFERYLDYAIQATETLAFVHCCLN PIIYFFLGEKFRKYILQLFKTCRGLFVLCQYCGLLQIYSADTPSSSYTQSTMDHDLHDAL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| ADReCS ID | BADD_A06414 ; BADD_A08478 | |||||
| HIT2.0 ID | T53O4A | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Mogamulizumab | Drug Info | Approved | Sezary syndrome | [2] | |
| Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
| 1 | RPT193 | Drug Info | Phase 2 | Asthma | [3] | |
| 2 | FLX475 | Drug Info | Phase 1/2 | Solid tumour/cancer | [4] | |
| 3 | ATLCAR.CD30.CCR4 cells | Drug Info | Phase 1 | Immune System disease | [5] | |
| 4 | GSK-2239633 | Drug Info | Phase 1 | Asthma | [6] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | AZD-1678 | Drug Info | Preclinical | Asthma | [7] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Inhibitor | [+] 15 Inhibitor drugs | + | ||||
| 1 | Mogamulizumab | Drug Info | [1] | |||
| 2 | 4-isopropyl-N-(naphthalen-1-yl)thiazol-2-amine | Drug Info | [11] | |||
| 3 | 4-methyl-N-(naphthalen-1-yl)thiazol-2-amine | Drug Info | [11] | |||
| 4 | 4-tert-butyl-N-(2-isopropylphenyl)thiazol-2-amine | Drug Info | [11] | |||
| 5 | 4-tert-butyl-N-(naphthalen-1-yl)oxazol-2-amine | Drug Info | [11] | |||
| 6 | 4-tert-butyl-N-(naphthalen-1-yl)thiazol-2-amine | Drug Info | [11] | |||
| 7 | 4-tert-butyl-N-m-tolylthiazol-2-amine | Drug Info | [11] | |||
| 8 | 4-tert-butyl-N-o-tolylthiazol-2-amine | Drug Info | [11] | |||
| 9 | 4-tert-butyl-N-phenylthiazol-2-amine | Drug Info | [11] | |||
| 10 | C-014C | Drug Info | [12] | |||
| 11 | N-(4-tert-butylthiazol-2-yl)-1H-indol-4-amine | Drug Info | [11] | |||
| 12 | N-(4-tert-butylthiazol-2-yl)isoquinolin-5-amine | Drug Info | [11] | |||
| 13 | N-(4-tert-butylthiazol-2-yl)quinolin-5-amine | Drug Info | [11] | |||
| 14 | N-(naphthalen-1-yl)-4-neopentylthiazol-2-amine | Drug Info | [11] | |||
| 15 | N-(naphthalen-1-yl)-4-phenylthiazol-2-amine | Drug Info | [11] | |||
| Antagonist | [+] 5 Antagonist drugs | + | ||||
| 1 | RPT193 | Drug Info | [3] | |||
| 2 | FLX475 | Drug Info | [8] | |||
| 3 | GSK-2239633 | Drug Info | [9] | |||
| 4 | AZD-1678 | Drug Info | [10] | |||
| 5 | AT-008 | Drug Info | [9] | |||
| CAR-T-Cell-Therapy(Dual specific) | [+] 1 CAR-T-Cell-Therapy(Dual specific) drugs | + | ||||
| 1 | ATLCAR.CD30.CCR4 cells | Drug Info | [5] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | RS-1748 | Drug Info | [9] | |||
| 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 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
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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 | ||
| Viral protein interaction with cytokine and cytokine receptor | hsa04061 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Chemokine signaling pathway | hsa04062 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 4.15E-04 |
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| Closeness centrality | 1.94E-01 | Radiality | 1.33E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.20E+01 | Topological coefficient | 3.33E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Cytokine-cytokine receptor interaction | |||||
| 2 | Chemokine signaling pathway | |||||
| 3 | Viral carcinogenesis | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Inflammation mediated by chemokine and cytokine signaling pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Chemokine receptors bind chemokines | |||||
| 2 | G alpha (i) signalling events | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | GPCRs, Class A Rhodopsin-like | |||||
| 2 | Peptide GPCRs | |||||
| 3 | GPCR ligand binding | |||||
| 4 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Mogamulizumab, a humanized mAb against C-C chemokine receptor 4 for the potential treatment of T-cell lymphomas and asthma. Curr Opin Mol Ther. 2010 Dec;12(6):770-9. | |||||
| REF 2 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 3 | ClinicalTrials.gov (NCT05399368) A Phase 2 Study to Evaluate the Efficacy and Safety of RPT193 as Monotherapy in Adults With Moderate-to-Severe Atopic Dermatitis. U.S.National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT03674567) Dose Escalation and Expansion Study of FLX475 Monotherapy and in Combination With Pembrolizumab. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT03602157) Study of CAR-T Cells Expressing CD30 and CCR4 for r/r CD30+ HL and NHL | |||||
| REF 6 | ClinicalTrials.gov (NCT01086462) Intravenous Microdose Pharmacokinetic (PK) Study With [14C]-GSK2239633. U.S. National Institutes of Health. | |||||
| 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 800030818) | |||||
| REF 8 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 9 | 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: 61). | |||||
| 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 800030818) | |||||
| REF 11 | Optimization of 2-aminothiazole derivatives as CCR4 antagonists. Bioorg Med Chem Lett. 2006 May 15;16(10):2800-3. | |||||
| REF 12 | Discovery of potent CCR4 antagonists: Synthesis and structure-activity relationship study of 2,4-diaminoquinazolines. Bioorg Med Chem. 2008 Jul 15;16(14):7021-32. | |||||
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