Target Information
| Target General Information | Top | |||||
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| Target ID |
T89988
(Former ID: TTDC00122)
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| Target Name |
C-C chemokine receptor type 2 (CCR2)
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| Synonyms |
Monocyte chemoattractant protein 1 receptor; MCP-1-R; Chemokine receptor CCR2B; CMKBR2; CD192; CCR-2; CC-CKR-2; C-C CKR-2
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| Gene Name |
CCR2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 10 Target-related Diseases | + | ||||
| 1 | Chronic kidney disease [ICD-11: GB61] | |||||
| 2 | Chronic obstructive pulmonary disease [ICD-11: CA22] | |||||
| 3 | Human immunodeficiency virus disease [ICD-11: 1C60-1C62] | |||||
| 4 | Metastatic tumour [ICD-11: 2D50-2E2Z] | |||||
| 5 | Multiple sclerosis [ICD-11: 8A40] | |||||
| 6 | Pancreatic cancer [ICD-11: 2C10] | |||||
| 7 | Chronic pain [ICD-11: MG30] | |||||
| 8 | Melanoma [ICD-11: 2C30] | |||||
| 9 | Rheumatoid arthritis [ICD-11: FA20] | |||||
| 10 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Its binding with CCL2 on monocytes and macrophages mediates chemotaxis and migration induction through the activation of the PI3K cascade, the small G protein Rac and lamellipodium protrusion. Also acts as a receptor for the beta-defensin DEFB106A/DEFB106B. Regulates the expression of T-cell inflammatory cytokines and T-cell differentiation, promoting the differentiation of T-cells into T-helper 17 cells (Th17) during inflammation. Faciltates the export of mature thymocytes by enhancing directional movement of thymocytes to sphingosine-1-phosphate stimulation and up-regulation of S1P1R expression; signals through the JAK-STAT pathway to regulate FOXO1 activity leading to an increased expression of S1P1R. Plays an important role in mediating peripheral nerve injury-induced neuropathic pain. Increases NMDA-mediated synaptic transmission in both dopamine D1 and D2 receptor-containing neurons, which may be caused by MAPK/ERK-dependent phosphorylation of GRIN2B/NMDAR2B. Mediates the recruitment of macrophages and monocytes to the injury site following brain injury. Key functional receptor for CCL2 but can also bind CCL7 and CCL12.
Click to Show/Hide
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MLSTSRSRFIRNTNESGEEVTTFFDYDYGAPCHKFDVKQIGAQLLPPLYSLVFIFGFVGN
MLVVLILINCKKLKCLTDIYLLNLAISDLLFLITLPLWAHSAANEWVFGNAMCKLFTGLY HIGYFGGIFFIILLTIDRYLAIVHAVFALKARTVTFGVVTSVITWLVAVFASVPGIIFTK CQKEDSVYVCGPYFPRGWNNFHTIMRNILGLVLPLLIMVICYSGILKTLLRCRNEKKRHR AVRVIFTIMIVYFLFWTPYNIVILLNTFQEFFGLSNCESTSQLDQATQVTETLGMTHCCI NPIIYAFVGEKFRSLFHIALGCRIAPLQKPVCGGPGVRPGKNVKVTTQGLLDGRGKGKSI GRAPEASLQDKEGA Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T20W1O | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 11 Clinical Trial Drugs | + | ||||
| 1 | AZD-2423 | Drug Info | Phase 2 | Chronic obstructive pulmonary disease | [2] | |
| 2 | BMS-813160 | Drug Info | Phase 2 | Diabetic nephropathy | [3] | |
| 3 | CCX-140 | Drug Info | Phase 2 | Diabetic nephropathy | [4] | |
| 4 | CCX872 | Drug Info | Phase 2 | Pancreatic tumour | [5] | |
| 5 | Cenicriviroc | Drug Info | Phase 2 | Human immunodeficiency virus infection | [6], [7] | |
| 6 | MK-0812 | Drug Info | Phase 2 | Multiple sclerosis | [8] | |
| 7 | MLN1202 | Drug Info | Phase 2 | Multiple sclerosis | [9] | |
| 8 | Aminoguanidine | Drug Info | Phase 1 | Diabetic retinopathy | [10] | |
| 9 | CNTX-6970 | Drug Info | Phase 1 | Inflammatory pain | [11] | |
| 10 | OPL-CCL2-LPM | Drug Info | Phase 1 | Arthritis | [12] | |
| 11 | TAK-202 | Drug Info | Phase 1 | Melanoma | [13] | |
| Discontinued Drug(s) | [+] 5 Discontinued Drugs | + | ||||
| 1 | CCX915 | Drug Info | Discontinued in Phase 1 | Multiple sclerosis | [14] | |
| 2 | INCB8696 | Drug Info | Discontinued in Phase 1 | Multiple sclerosis | [15] | |
| 3 | AZD-6942 | Drug Info | Terminated | Rheumatoid arthritis | [18] | |
| 4 | INCB3344 | Drug Info | Terminated | Arteriosclerosis | [19], [20] | |
| 5 | SB-282241 | Drug Info | Terminated | Inflammation | [21], [22] | |
| Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
| 1 | MCP-1 | Drug Info | Preclinical | Rheumatoid arthritis | [16] | |
| 2 | RS-504393 | Drug Info | Preclinical | Chronic obstructive pulmonary disease | [16], [17] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Antagonist | [+] 22 Antagonist drugs | + | ||||
| 1 | AZD-2423 | Drug Info | [23] | |||
| 2 | CCX-140 | Drug Info | [1] | |||
| 3 | Cenicriviroc | Drug Info | [27] | |||
| 4 | MK-0812 | Drug Info | [28] | |||
| 5 | MLN1202 | Drug Info | [16] | |||
| 6 | Aminoguanidine | Drug Info | [29] | |||
| 7 | CNTX-6970 | Drug Info | [11] | |||
| 8 | TAK-202 | Drug Info | [5], [13] | |||
| 9 | CCX915 | Drug Info | [31] | |||
| 10 | INCB8696 | Drug Info | [32] | |||
| 11 | MCP-1 | Drug Info | [16] | |||
| 12 | RS-504393 | Drug Info | [16], [33] | |||
| 13 | AZD-6942 | Drug Info | [34] | |||
| 14 | INCB3344 | Drug Info | [35] | |||
| 15 | SB-282241 | Drug Info | [34] | |||
| 16 | BMS-A | Drug Info | [37] | |||
| 17 | GSK-1344386B | Drug Info | [37] | |||
| 18 | INCB-10820 | Drug Info | [37] | |||
| 19 | RS-102895 | Drug Info | [39] | |||
| 20 | RS-136270 | Drug Info | [39] | |||
| 21 | Teijin-lead_cmp_5 | Drug Info | [22] | |||
| 22 | viral macrophage inflammatory protein-II | Drug Info | [40] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | BMS-813160 | Drug Info | [24], [25] | |||
| 2 | OPL-CCL2-LPM | Drug Info | [30] | |||
| 3 | RAP-103 | Drug Info | [37] | |||
| 4 | RAP-310 | Drug Info | [37] | |||
| Inhibitor | [+] 5 Inhibitor drugs | + | ||||
| 1 | CCX872 | Drug Info | [26] | |||
| 2 | (R)-3-(1'-Adamantanecarbonyl)amino-caprolactam | Drug Info | [36] | |||
| 3 | (S)-3-(1'-Adamantanecarbonyl)amino-caprolactam | Drug Info | [36] | |||
| 4 | (S)-3-(2',2'-Dimethyl-propionyl)amino-caprolactam | Drug Info | [36] | |||
| 5 | NSC-651016 | Drug Info | [38] | |||
| 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 | |||||
|---|---|---|---|---|---|---|
| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
|---|---|---|---|---|---|---|
| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Cytokine-cytokine receptor interaction | |||||
| 2 | Chemokine signaling pathway | |||||
| NetPath Pathway | [+] 5 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| 2 | IL2 Signaling Pathway | |||||
| 3 | TGF_beta_Receptor Signaling Pathway | |||||
| 4 | Leptin Signaling Pathway | |||||
| 5 | RANKL Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Inflammation mediated by chemokine and cytokine signaling pathway | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Beta defensins | |||||
| 2 | Chemokine receptors bind chemokines | |||||
| 3 | G alpha (i) signalling events | |||||
| WikiPathways | [+] 6 WikiPathways | + | ||||
| 1 | GPCRs, Class A Rhodopsin-like | |||||
| 2 | Defensins | |||||
| 3 | Spinal Cord Injury | |||||
| 4 | Peptide GPCRs | |||||
| 5 | GPCR ligand binding | |||||
| 6 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Present and future in the treatment of diabetic kidney disease. J Diabetes Res. 2015;2015:801348. | |||||
| REF 2 | ClinicalTrials.gov (NCT01215279) AZD2423 Safety and Tolerability Study in Patients With Moderate and Severe Chronic Obstructive Pulmonary Disease(COPD) in AstraZeneca. | |||||
| REF 3 | ClinicalTrials.gov (NCT01752985) Study to Evaluate the Effects of BMS-813160 on Protein Loss in the Urine of Subjects With Type 2 Diabetes and Diabetic Kidney Disease. U.S. National Institutes of Health. | |||||
| REF 4 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018498) | |||||
| REF 5 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 6 | 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: 801). | |||||
| REF 7 | The dual CCR5 and CCR2 inhibitor cenicriviroc does not redistribute HIV into extracellular space: implications for plasma viral load and intracellular DNA decline. J Antimicrob Chemother. 2015 Mar;70(3):750-6. | |||||
| REF 8 | ClinicalTrials.gov (NCT00239655) A Study to Assess the Effects of MK0812 on Disease Activity in Patients With Relapsing-Remitting Multiple Sclerosis as Measured by Magnetic Resonance Imaging (MRI). U.S. National Institutes of Health. | |||||
| REF 9 | Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis. Expert Opin Emerg Drugs. 2009 Sep;14(3):471-9. | |||||
| REF 10 | ClinicalTrials.gov (NCT02099981) Restoration of Retinal Vascular Responses in Type 1 Diabetic Patients in University of Minnesota - Clinical and Translational Science Institute. | |||||
| REF 11 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030092) | |||||
| REF 13 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 14 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800035649) | |||||
| REF 15 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024340) | |||||
| REF 16 | Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91. | |||||
| REF 17 | 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: 781). | |||||
| REF 18 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016328) | |||||
| REF 19 | 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: 777). | |||||
| REF 20 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800035662) | |||||
| REF 21 | 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: 782). | |||||
| REF 22 | CCR2: characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach. J Med Chem. 2003 Sep 11;46(19):4070-86. | |||||
| REF 23 | CA patent application no. 841416, Method of selecting therapeutic indications. | |||||
| REF 24 | A dual CCR2/CCR5 chemokine antagonist, BMS-813160. Expert Opin Ther Pat. 2011 Dec;21(12):1919-24. | |||||
| REF 25 | Methods for improving thymic recovery and preventing and treating graft versus host disease using ccr2 and ccr5 antagonists | |||||
| REF 26 | Therapeutic use of a clinical stage CCR2 inhibitor, CCX872, in obesity-associated steatohepatitis. The Lancet Volume 383, Supplement 1, 26 February 2014, Pages S78. | |||||
| REF 27 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 28 | Assessment of chemokine receptor function on monocytes in whole blood: In vitro and ex vivo evaluations of a CCR2 antagonist. J Immunol Methods. 2010 Jan 31;352(1-2):101-10. | |||||
| REF 29 | Incyte Announces Second Quarter 2005 Financial Results; Reports Positive Phase IIb Results for Reverset in Treatment-Experienced HIV Patients. Incyte Corporation. 2005. | |||||
| REF 30 | Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis. Clin Exp Immunol. 2009 February; 155(2): 295-303. | |||||
| REF 31 | Marketed and experimental medicines for the treatment of multiple sclerosis. The Association of the British Pharmaceutical Industry. 2009. | |||||
| REF 32 | Incyte. Product Development Pipeline. | |||||
| REF 33 | Beneficial or detrimental effects of carotenoids contained in food: cell culture models. Mini Rev Med Chem. 2007 Nov;7(11):1120-8. | |||||
| REF 34 | Patent EP2727944 A1. | |||||
| REF 35 | Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile. Bioorg Med Chem Lett. 2011 May 1;21(9):2626-30. | |||||
| REF 36 | Highly potent, orally available anti-inflammatory broad-spectrum chemokine inhibitors. J Med Chem. 2009 Jun 11;52(11):3591-5. | |||||
| REF 37 | 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: 59). | |||||
| REF 38 | Inhibition of in vitro and in vivo HIV replication by a distamycin analogue that interferes with chemokine receptor function: a candidate for chemo... J Med Chem. 1998 Jun 18;41(13):2184-93. | |||||
| REF 39 | Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within t... J Biol Chem. 2000 Aug 18;275(33):25562-71. | |||||
| REF 40 | A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science. 1997 Sep 12;277(5332):1656-9. | |||||
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