Target Information
| Target General Information | Top | |||||
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| Target ID |
T16016
(Former ID: TTDC00215)
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| Target Name |
C-C chemokine receptor type 1 (CCR1)
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| Synonyms |
SCYAR1; RANTES-R; Macrophage inflammatory protein-1 alpha receptor; Macrophage inflammatory protein 1-alpha receptor; MIP-1alpha-R; LD78 receptor; HM145; Chemokine receptor CCR1; CMKR1; CMKBR1; CD191; CCR-1; CC-CKR-1; C-C CKR-1
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| Gene Name |
CCR1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Diabetes mellitus [ICD-11: 5A10] | |||||
| 2 | Rheumatoid arthritis [ICD-11: FA20] | |||||
| Function |
Binds to MIP-1-alpha, MIP-1-delta, RANTES, and MCP-3 and, less efficiently, to MIP-1-beta or MCP-1 and subsequently transduces a signal by increasing the intracellular calcium ions level. Responsible for affecting stem cell proliferation. Receptor for a C-C type chemokine.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
METPNTTEDYDTTTEFDYGDATPCQKVNERAFGAQLLPPLYSLVFVIGLVGNILVVLVLV
QYKRLKNMTSIYLLNLAISDLLFLFTLPFWIDYKLKDDWVFGDAMCKILSGFYYTGLYSE IFFIILLTIDRYLAIVHAVFALRARTVTFGVITSIIIWALAILASMPGLYFSKTQWEFTH HTCSLHFPHESLREWKLFQALKLNLFGLVLPLLVMIICYTGIIKILLRRPNEKKSKAVRL IFVIMIIFFLFWTPYNLTILISVFQDFLFTHECEQSRHLDLAVQVTEVIAYTHCCVNPVI YAFVGERFRKYLRQLFHRRVAVHLVKWLPFLSVDRLERVSSTSPSTGEHELSAGF Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T47WWK | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | BMS-817399 | Drug Info | Phase 2 | Rheumatoid arthritis | [2] | |
| 2 | CCX-354 | Drug Info | Phase 2 | Autoimmune diabetes | [3] | |
| 3 | AVE1701 | Drug Info | Phase 1 | Rheumatoid arthritis | [4] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | AZD4818 | Drug Info | Discontinued in Phase 2 | Chronic obstructive pulmonary disease | [5] | |
| 2 | MLN3897 | Drug Info | Discontinued in Phase 2 | Rheumatoid arthritis | [4] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | BMS-817399 | Drug Info | [6] | |||
| Antagonist | [+] 5 Antagonist drugs | + | ||||
| 1 | CCX-354 | Drug Info | [1] | |||
| 2 | AVE1701 | Drug Info | [4] | |||
| 3 | AZD4818 | Drug Info | [7] | |||
| 4 | MLN3897 | Drug Info | [4] | |||
| 5 | BX 471 | Drug Info | [10] | |||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | COSALANE | Drug Info | [8] | |||
| 2 | A-987306 | Drug Info | [9] | |||
| 3 | Cosalane derivative | Drug Info | [8] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Cholesterol | Ligand Info | |||||
| Structure Description | Cryo-EM structure of the CCL15(26-92) bound CCR1-Gi complex | PDB:7VL9 | ||||
| Method | Electron microscopy | Resolution | 2.60 Å | Mutation | Yes | [11] |
| PDB Sequence |
DYGDATPCQK
26 VNERAFGAQL36 LPPLYSLVFV46 IGLVGNILVV56 LVLVQYKRLK66 NMTSIYLLNL 76 AISDLLFLFT86 LPFWIDYKLK96 DDWVFGDAMC106 KILSGFYYTG116 LYSEIFFIIL 126 LTIDRYLAIV136 HAVFALRART146 VTFGVITSII156 IWALAILASM166 PGLYFSKTQW 176 EFTHHTCSLH186 FPHESLREWK196 LFQALKLNLF206 GLVLPLLVMI216 ICYTGIIKIL 226 LRRPNEKKSK236 AVRLIFVIMI246 IFFLFWTPYN256 LTILISVFQD266 FLFTHECEQS 276 RHLDLAVQVT286 EVIAYTHCCV296 NPVIYAFVGE306 RFRKYLRQLF316 HR |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| 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 | 12 | Degree centrality | 1.29E-03 | Betweenness centrality | 4.76E-04 |
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| Closeness centrality | 1.95E-01 | Radiality | 1.33E+01 | Clustering coefficient | 1.36E-01 |
| Neighborhood connectivity | 1.40E+01 | Topological coefficient | 1.97E-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 | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Cytokine-cytokine receptor interaction | |||||
| 2 | Chemokine signaling pathway | |||||
| NetPath Pathway | [+] 5 NetPath Pathways | + | ||||
| 1 | IL5 Signaling Pathway | |||||
| 2 | TCR Signaling Pathway | |||||
| 3 | IL2 Signaling Pathway | |||||
| 4 | TNFalpha Signaling Pathway | |||||
| 5 | Leptin Signaling Pathway | |||||
| 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 | Chemokine receptor CCR1 antagonist CCX354-C treatment for rheumatoid arthritis: CARAT-2, a randomised, placebo controlled clinical trial. Ann Rheum Dis. 2013 Mar;72(3):337-44. | |||||
| REF 2 | ClinicalTrials.gov (NCT01404585) Proof-of-Concept Study With BMS-817399 to Treat Moderate to Severe Rheumatoid Arthritis. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT01242917) A Study to Evaluate the Safety and Efficacy of CCX354-C in Subjects With Rheumatoid Arthritis Partially Responsive to Methotrexate Therapy. U.S. National Institutes of Health. | |||||
| REF 4 | Emerging drugs for rheumatoid arthritis. Expert Opin Emerg Drugs. 2008 Mar;13(1):175-96. | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025769) | |||||
| REF 6 | Discovery of the CCR1 antagonist, BMS-817399, for the treatment of rheumatoid arthritis. J Med Chem. 2014 Sep 25;57(18):7550-64. | |||||
| REF 7 | Clinical pipeline report, company report or official report of AstraZeneca (2009). | |||||
| REF 8 | Inhibition of RANTES/CCR1-mediated chemotaxis by cosalane and related compounds. Bioorg Med Chem Lett. 2001 Jan 8;11(1):59-62. | |||||
| REF 9 | cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain... J Med Chem. 2008 Nov 27;51(22):7094-8. | |||||
| REF 10 | Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem. 2000 Jun 23;275(25):19000-8. | |||||
| REF 11 | Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1. Nat Chem Biol. 2022 Mar;18(3):264-271. | |||||
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