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Target has curated data in GtoImmuPdb
Target id: 61
Nomenclature: CCR4
Family: Chemokine receptors
Annotation status:
Annotated and reviewed, awaiting update
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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 360 | 3p22.3 | CCR4 | C-C motif chemokine receptor 4 | 24 |
| Mouse | 7 | 360 | 9 64.49 cM | Ccr4 | C-C motif chemokine receptor 4 | |
| Rat | 7 | 360 | 8q32 | Ccr4 | C-C motif chemokine receptor 4 | |
| Previous and Unofficial Names |
| CD194 | ChemR13 | C-C chemokine receptor 4 | CC CKR4 | chemokine (C-C motif) receptor 4 |
| Database Links |
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| Specialist databases | |
| GPCRdb | ccr4_human (Hs), ccr4_mouse (Mm) |
| Other databases | |
| Alphafold | P51679 (Hs), P51680 (Mm) |
| ChEMBL Target | CHEMBL2414 (Hs), CHEMBL5410 (Mm) |
| Ensembl Gene | ENSG00000183813 (Hs), ENSMUSG00000047898 (Mm), ENSRNOG00000010315 (Rn) |
| Entrez Gene | 1233 (Hs), 12773 (Mm), 171054 (Rn) |
| Human Protein Atlas | ENSG00000183813 (Hs) |
| KEGG Gene | hsa:1233 (Hs), mmu:12773 (Mm), rno:171054 (Rn) |
| OMIM | 604836 (Hs) |
| Pharos | P51679 (Hs) |
| RefSeq Nucleotide | NM_005508 (Hs), NM_009916 (Mm), NM_133532 (Rn) |
| RefSeq Protein | NP_005499 (Hs), NP_034046 (Mm), NP_598216 (Rn) |
| UniProtKB | P51679 (Hs), P51680 (Mm) |
| Wikipedia | CCR4 (Hs) |
| Natural/Endogenous Ligands |
| CCL17 {Sp: Human} |
| CCL22 {Sp: Human} , CCL22 {Sp: Mouse} |
Download all structure-activity data for this target as a CSV file 
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Immunopharmacology Comments |
| CCR4 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. In disease states CCR4 is involved in recruiting T helper type 2 cell (Th2) subsets in autoimmune disorders such as asthma, allergic rhinitis, and atopic dermatitis [27], and recruiting highly immunosuppressive CD4+/CD25+/FOXP3+ regulatory T cells (Treg) cells to the tumour microenvironment [14]. As such antagonists of CCR4 are under investigation for clinical utility in inflammatory diseases and cancer. Of note is the approval of mogamulizumab, an anti-CCR4 monoclonal immuno-oncology agent, although its use can produce damaging side effects via depletion of Treg cells and their vital immune functions outwith the targeted tissues. Small molecule CCR4 antagonists have also been developed e.g. AZD1678 and AZD2098, and GSK2239633A which was advanced to Phase 1 clinical trial for asthma but not progressed further [4]. |
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| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
| Gi/Go family | Calcium channel |
| References: 21 | |
| Tissue Distribution
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| Expression Datasets |
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| Functional Assays
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| Physiological Functions
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||
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1. Antoniu SA. (2010) Mogamulizumab, a humanized mAb against C-C chemokine receptor 4 for the potential treatment of T-cell lymphomas and asthma. Curr Opin Mol Ther, 12 (6): 770-9. [PMID:21154168]
2. Ayehunie S, Garcia-Zepeda EA, Hoxie JA, Horuk R, Kupper TS, Luster AD, Ruprecht RM. (1997) Human immunodeficiency virus-1 entry into purified blood dendritic cells through CC and CXC chemokine coreceptors. Blood, 90 (4): 1379-86. [PMID:9269754]
3. Beck HP, Biannic B, Bui MHT, Hu DX, Ketcham JM, Powers JP, Reilly MK, Robles-Resendiz O, Shunatona HP, Walker JR et al.. (2018) Chemokine receptor modulators and uses thereof. Patent number: WO2018022992A1. Assignee: Flx Bio, Inc.. Priority date: 29/07/2016. Publication date: 01/02/2018.
4. Cahn A, Hodgson S, Wilson R, Robertson J, Watson J, Beerahee M, Hughes SC, Young G, Graves R, Hall D et al.. (2013) Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol Toxicol, 14: 14. DOI: 10.1186/2050-6511-14-14 [PMID:23448278]
5. Campbell JJ, Haraldsen G, Pan J, Rottman J, Qin S, Ponath P, Andrew DP, Warnke R, Ruffing N, Kassam N et al.. (1999) The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature, 400 (6746): 776-80. [PMID:10466728]
6. Campbell JJ, Pan J, Butcher EC. (1999) Cutting edge: developmental switches in chemokine responses during T cell maturation. J Immunol, 163 (5): 2353-7. [PMID:10452965]
7. Chvatchko Y, Hoogewerf AJ, Meyer A, Alouani S, Juillard P, Buser R, Conquet F, Proudfoot AE, Wells TN, Power CA. (2000) A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock. J Exp Med, 191 (10): 1755-64. [PMID:10811868]
8. Clemetson KJ, Clemetson JM, Proudfoot AE, Power CA, Baggiolini M, Wells TN. (2000) Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets. Blood, 96 (13): 4046-54. [PMID:11110672]
9. Corcione A, Tortolina G, Bonecchi R, Battilana N, Taborelli G, Malavasi F, Sozzani S, Ottonello L, Dallegri F, Pistoia V. (2002) Chemotaxis of human tonsil B lymphocytes to CC chemokine receptor (CCR) 1, CCR2 and CCR4 ligands is restricted to non-germinal center cells. Int Immunol, 14: 883-892. [PMID:12147625]
10. Flynn G, Maru S, Loughlin J, Romero IA, Male D. (2003) Regulation of chemokine receptor expression in human microglia and astrocytes. J Neuroimmunol, 136 (1-2): 84-93. [PMID:12620646]
11. Huber TB, Reinhardt HC, Exner M, Burger JA, Kerjaschki D, Saleem MA, Pavenstädt H. (2002) Expression of functional CCR and CXCR chemokine receptors in podocytes. J Immunol, 168 (12): 6244-52. [PMID:12055238]
12. Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia F, D'Ambrosio D. (2001) Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med, 194 (6): 847-53. [PMID:11560999]
13. Imai T, Chantry D, Raport CJ, Wood CL, Nishimura M, Godiska R, Yoshie O, Gray PW. (1998) Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4. J Biol Chem, 273 (3): 1764-8. [PMID:9430724]
14. Ishida T, Ueda R. (2006) CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci, 97 (11): 1139-46. [PMID:16952304]
15. Jackson JJ, Ketcham JM, Okano A, Reilly MK, Robles-Resendiz O, Schwarz JB, Tivitmahaisoon P, Wustrow DJ, Younai A, Zibinsky M. (2019) Chemokine receptor modulators and uses thereof. Patent number: WO2019147862A1. Assignee: Flx Bio, Inc.. Priority date: 24/01/2019. Publication date: 01/08/2019.
16. Jackson JJ, Ketcham JM, Younai A, Abraham B, Biannic B, Beck HP, Bui MHT, Chian D, Cutler G, Diokno R et al.. (2019) Discovery of a Potent and Selective CCR4 Antagonist That Inhibits Treg Trafficking into the Tumor Microenvironment. J Med Chem, 62 (13): 6190-6213. [PMID:31259550]
17. Juremalm M, Olsson N, Nilsson G. (2002) Selective CCL5/RANTES-induced mast cell migration through interactions with chemokine receptors CCR1 and CCR4. Biochem Biophys Res Commun, 297 (3): 480-5. [PMID:12270118]
18. Kindon N, Andrews G, Baxter A, Cheshire D, Hemsley P, Johnson T, Liu YZ, McGinnity D, McHale M, Mete A et al.. (2017) Discovery of AZD-2098 and AZD-1678, Two Potent and Bioavailable CCR4 Receptor Antagonists. ACS Med Chem Lett, 8 (9): 981-986. [PMID:28947948]
19. Meucci O, Fatatis A, Simen AA, Bushell TJ, Gray PW, Miller RJ. (1998) Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc Natl Acad Sci USA, 95 (24): 14500-5. [PMID:9826729]
20. Nanki T, Lipsky PE. (2000) Lack of correlation between chemokine receptor and T(h)1/T(h)2 cytokine expression by individual memory T cells. Int Immunol, 12 (12): 1659-67. [PMID:11099305]
21. Oh SB, Endoh T, Simen AA, Ren D, Miller RJ. (2002) Regulation of calcium currents by chemokines and their receptors. J Neuroimmunol, 123 (1-2): 66-75. [PMID:11880151]
22. Procopiou PA, Barrett JW, Barton NP, Begg M, Clapham D, Copley RC, Ford AJ, Graves RH, Hall DA, Hancock AP et al.. (2013) Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists. J Med Chem, 56 (5): 1946-60. [PMID:23409871]
23. Salcedo R, Young HA, Ponce ML, Ward JM, Kleinman HK, Murphy WJ, Oppenheim JJ. (2001) Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. J Immunol, 166 (12): 7571-8. [PMID:11390513]
24. Samson M, Soularue P, Vassart G, Parmentier M. (1996) The genes encoding the human CC-chemokine receptors CC-CKR1 to CC-CKR5 (CMKBR1-CMKBR5) are clustered in the p21.3-p24 region of chromosome 3. Genomics, 36: 522-526. [PMID:8884276]
25. Schuh JM, Power C, Proudfoot AE, Kunkel SL, Lukacs NW, Hogaboam CM. (2002) Airway hyperresponsiveness, but not airway remodeling, is attenuated during chronic pulmonary allergic responses to Aspergillus in CCR4-/- mice. FASEB J, 16 (10): 1313-5. [PMID:12154006]
26. Shitara K, Nakamura K, Hosaka E, Tanaka A, Koike M. (2009) Monoclonal antibodies which preferentially bind to chemokine receptors, used for immunotherapy, as antiinflammatory, aniticarcinogenic agents and for prophylaxis of respiratory system disorders or antiallergens. Patent number: US7504104. Assignee: Kyowa Hakko Kogyo Co., Ltd. Priority date: 31/08/2001. Publication date: 17/01/2010.
27. Solari R, Pease JE. (2015) Targeting chemokine receptors in disease--a case study of CCR4. Eur J Pharmacol, 763 (Pt B): 169-77. [PMID:25981299]
28. Wang Y, Zhang Y, Yang X, Han W, Liu Y, Xu Q, Zhao R, Di C, Song Q, Ma D. (2006) Chemokine-like factor 1 is a functional ligand for CC chemokine receptor 4 (CCR4). Life Sci, 78 (6): 614-21. [PMID:16137713]
29. Yano S, Mentaverri R, Kanuparthi D, Bandyopadhyay S, Rivera A, Brown EM, Chattopadhyay N. (2005) Functional expression of beta-chemokine receptors in osteoblasts: role of regulated upon activation, normal T cell expressed and secreted (RANTES) in osteoblasts and regulation of its secretion by osteoblasts and osteoclasts. Endocrinology, 146 (5): 2324-35. [PMID:15718270]
30. Yokoyama K, Ishikawa N, Igarashi S, Kawano N, Masuda N, Hamaguchi W, Yamasaki S, Koganemaru Y, Hattori K, Miyazaki T et al.. (2009) Potent and orally bioavailable CCR4 antagonists: Synthesis and structure-activity relationship study of 2-aminoquinazolines. Bioorg Med Chem, 17 (1): 64-73. [PMID:19081254]
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Last modified on 16/08/2023.
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