CXCR4 | Chemokine receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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CXCR4

target has curated data in GtoImmuPdb

Target id: 71

Nomenclature: CXCR4

Family: Chemokine receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Contents:

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 352 2q21 CXCR4 C-X-C motif chemokine receptor 4 16,40
Mouse 7 359 1 E3 Cxcr4 chemokine (C-X-C motif) receptor 4 22,46
Rat 7 349 13q12 Cxcr4 C-X-C motif chemokine receptor 4 31,64
Previous and Unofficial Names
fusin [8,16,22] | LCR1 [64] | LESTR [40,46] | HM89 | HUMSTSR | CD184 | NPY3R | NPYY3R | CXCR-4 | CXC-R4 | SDF-1 receptor | stromal cell-derived factor 1 receptor | Cmkar4 | HSY3RR | chemokine (C-X-C motif) receptor 4
Database Links
Specialist databases
GPCRDB cxcr4_human (Hs), cxcr4_mouse (Mm), cxcr4_rat (Rn)
Other databases
ChEMBL Target CHEMBL2107 (Hs), CHEMBL1250365 (Mm), CHEMBL5556 (Rn)
DrugBank Target P61073 (Hs)
Ensembl Gene ENSG00000121966 (Hs), ENSMUSG00000045382 (Mm), ENSRNOG00000003866 (Rn)
Entrez Gene 7852 (Hs), 12767 (Mm), 60628 (Rn)
Human Protein Atlas ENSG00000121966 (Hs)
KEGG Gene hsa:7852 (Hs), mmu:12767 (Mm), rno:60628 (Rn)
OMIM 162643 (Hs)
Orphanet ORPHA120914 (Hs)
RefSeq Nucleotide NM_003467 (Hs), NM_009911 (Mm), NM_022205 (Rn)
RefSeq Protein NP_003458 (Hs), NP_034041 (Mm), NP_071541 (Rn)
SynPHARM 6612 (in complex with isothiourea-1t)
6614 (in complex with isothiourea-1t)
UniProtKB P61073 (Hs), P70658 (Mm), O08565 (Rn)
Wikipedia CXCR4 (Hs)
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  CXCR4 chemokine receptor in complex with small molecule antagonist
PDB Id:  3ODU
Ligand:  isothiourea-1t
Resolution:  2.5Å
Species:  Human
References:  66
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the CXCR4 chemokine receptor in complex with a cyclic peptide antagonist CVX15
PDB Id:  3OE0
Resolution:  2.9Å
Species:  Human
References:  66
Natural/Endogenous Ligands
CXCL12γ {Sp: Human}
CXCL12δ {Sp: Human}
CXCL12ε {Sp: Human}
CXCL12φ {Sp: Human}
CXCL12β {Sp: Human}
CXCL12α {Sp: Human}
CXCL12 {Sp: Mouse}
Comments: SDF1α and SDF1β are the active isomers of CXCL12

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CXCL12α {Sp: Human} Hs Full agonist 7.7 – 8.2 pKd 25,41
⤷ pKd 7.7 – 8.2 [25,41]
[125I]CXCL12α (human) Hs Full agonist 7.4 – 8.4 pKd 14,25,65
⤷ pKd 8.1 – 8.4 (Kd 7.94x10-9 – 3.98x10-9 M) [14,25]
pKd 7.4 (Kd 3.58x10-8 M) [65]
[125I]CXCL12β (human) Hs Full agonist 7.9 pKd 25
⤷ pKd 7.9 [25]
CXCL12β {Sp: Human} Hs Full agonist 7.9 pKd 25
⤷ pKd 7.9 (Kd 1.37x10-8 M) [25]
CXCL12H25R (monomer) Hs Agonist 7.8 pKd 15
⤷ pKd 7.8 (Kd 1.5x10-8 M) [15]
CXCL122 (dimer) Hs Partial agonist <6.0 pKd 15
⤷ pKd <6.0 (Kd >1x10-6 M) [15]
CXCL12-(1-17) Hs Full agonist 6.1 pKi 41
⤷ pKi 6.1 [41]
CXCL12-(1-9) dimer Hs Full agonist 6.1 pKi 41
⤷ pKi 6.1 [41]
CXCL12-(1-9) Hs Full agonist 4.9 pKi 41
⤷ pKi 4.9 [41]
CXCL12α {Sp: Human} Hs Agonist 9.3 pIC50 1
⤷ pIC50 9.3 (IC50 5x10-10 M) [1]
Description: Measuring CXCL12-induced displacement of CXCR4-bound 125I-CXCL12 from membranes prepared from HEK293T cells expressing human CXCR4.
ALX40-4C Hs Partial agonist 6.1 pIC50 71
⤷ pIC50 6.1 (IC50 7.94x10-7 M) [71]
CXCL12γ {Sp: Human} Hs Agonist - - 52,68
⤷ [52,68]
CXCL12δ {Sp: Human} Hs Agonist - - 68
⤷ [68]
CXCL12ε {Sp: Human} Hs Agonist - - 68
⤷ [68]
CXCL12φ {Sp: Human} Hs Agonist - - 68
⤷ [68]
Agonist Comments
SDF-1α and SDF-1β are both referred to as CXCL12 and they have equivalent binding affinity and potency [25].
The CXCL12 isoforms (δ, γ, ε and φ) identified by Yu et al. (2006) were shown to stimulate cell migration in a CXCR4-dependent fashion [68].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SDF1 P2G Hs Antagonist 8.1 pKd 11
⤷ pKd 8.1 (Kd 9x10-9 M) [11]
mavorixafor Hs Antagonist 8.0 pKi 65
⤷ pKi 8.0 (Ki 1.1x10-8 M) [65]
Description: Assay using 125I-SDF-1α as tracer, in Cf2Th cells expressing hCXCR4.
plerixafor Hs Antagonist 6.7 – 7.0 pKi 1,71
⤷ pKi 7.0 [71]
pKi 6.7 (Ki 1.99x10-7 M) [1]
SDF-1, 1-9[P2G] dimer Hs Antagonist 5.6 pKi 41
⤷ pKi 5.6 [41]
isothiourea-1t Hs Antagonist 9.0 pEC50 60
⤷ pEC50 9.0 [60]
isothiourea-1a Hs Antagonist 8.0 pEC50 60
⤷ pEC50 8.0 [60]
T134 Hs Antagonist 8.4 pIC50 59
⤷ pIC50 8.4 (IC50 3.98x10-9 M) [59]
T140 Hs Inverse agonist 7.8 – 8.6 pIC50 59,71
⤷ pIC50 7.8 – 8.6 [59,71]
viral macrophage inflammatory protein-II Hs Antagonist 8.2 pIC50 34
⤷ pIC50 8.2 [34]
TIQ-15 Hs Antagonist 8.2 pIC50 45
⤷ pIC50 8.2 (IC50 6.25x10-9 M) [45]
Description: Measuring antagonist-mediated inhibition of CXCL12-induced calcium flux in human T lymphoblast CCRF-CEM cells.
isothiourea-1t Hs Antagonist 8.0 – 8.1 pIC50 1,60
⤷ pIC50 8.0 – 8.1 (IC50 1x10-8 – 7.9x10-9 M) [1,60]
compound 46c [PMID: 29350534] Mm Antagonist 8.0 pIC50 45
⤷ pIC50 8.0 (IC50 9.24x10-9 M) [45]
isothiourea-1t Rn Antagonist 8.0 pIC50 60
⤷ pIC50 8.0 [60]
mavorixafor Hs Antagonist 7.9 pIC50 56
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [56]
Description: Displacement of [125I]SDF-1α binding from CXCR4 in human CEM-CCRF cells by liquid scintillation counting.
compound 46c [PMID: 29350534] Hs Antagonist 7.8 pIC50 45
⤷ pIC50 7.8 (IC50 1.55x10-8 M) [45]
Description: Measuring antagonist-mediated inhibition of CXCL12-induced calcium flux in human T lymphoblast CCRF-CEM cells.
isothiourea-1a Hs Antagonist 7.3 pIC50 60
⤷ pIC50 7.3 [60]
T22 Hs Antagonist 7.3 pIC50 59
⤷ pIC50 7.3 [59]
CX549 Hs Antagonist ~7.3 pIC50 67
⤷ pIC50 ~7.3 (IC50 ~5x10-8 M) [67]
isothiourea-1a Rn Antagonist 7.3 pIC50 60
⤷ pIC50 7.3 [60]
CXCR4 antagonist 22 Hs Antagonist 6.3 pIC50 1
⤷ pIC50 6.3 (IC50 5x10-7 M) [1]
Description: Displacement of CXCR4-bound 125I-CXCL12 from membranes prepared from HEK293T cells expressing human CXCR4.
View species-specific antagonist tables
Antagonist Comments
AMD3100 (plerixafor, Mozobil®) was approved by the US FDA in December 2008 for hematopoietic progenitor cell mobilisation [38].
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
ulocuplumab Hs Binding 8.6 pEC50 36
⤷ pEC50 8.6 (EC50 2.26x10-9 M) [36]
Description: Measuring displacement of iodinated SDF-1 from exogenously expressed CXCR4 in vitro.
Antibody Comments
Using their i-body platform, AdAlta have identified an anti-CXCR4 antibody (AD-114) that has proven effective as an anti-fibrotic agent in preclinical testing, in animal models of idiopathic pulmonary fibrosis (IPF) [18] and retinal fibrosis associated with age-related macular degeneration. AD-114 represents a novel mechanism of action for IPF, and a "first in class" therapy for this indication.
Immunopharmacology Comments
CXCR4 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. Due to its role in cancer cell homing and metastasis the CXCR4-CXCL12 axis is a potential target for cancer therapy [51,54,61-62]. This is exemplified by the development of ulocuplumab as an anti-cancer biologic therapy. Targeting the CXCR4-CXCL12 axis also offers the possibility of modulating the immune response in non-cancer indications [39,50,70].
Immuno Process Associations
Immuno Process:  Barrier integrity
GO Annotations:  Associated to 3 GO processes
GO:0019064 fusion of virus membrane with host plasma membrane TAS
GO:0030260 entry into host cell TAS
click arrow to show/hide IEA associations
GO:0001618 virus receptor activity IEA
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0002407 dendritic cell chemotaxis TAS
GO:0006954 inflammatory response TAS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 5 GO processes
GO:0016493 C-C chemokine receptor activity IBA
GO:0016494 C-X-C chemokine receptor activity NAS
GO:0038147 C-X-C motif chemokine 12 receptor activity IDA
GO:0038160 CXCL12-activated CXCR4 signaling pathway IDA
GO:0071345 cellular response to cytokine stimulus IDA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 5 GO processes
GO:0002407 dendritic cell chemotaxis TAS
GO:0016493 C-C chemokine receptor activity IBA
GO:0016494 C-X-C chemokine receptor activity NAS
GO:0038147 C-X-C motif chemokine 12 receptor activity IDA
GO:0038160 CXCL12-activated CXCR4 signaling pathway IDA
Immuno Disease Associations
Disease Name:  WHIM syndrome
Disease Synonyms:  no synonynms
Comment:  Mutations in CXCR4 that augment its activity have been identified in patients with WHIM syndrome. Such mutations can impair CXCR4/β-arrestin interaction and β-arrestin-mediated signal attenuation. This effect leads to defective desensitization and internalization of CXCR4 in response to ligand (CXCL12; SDF1) activation; in effect, increased CXCR4 activity.
Disease X-refs:  OMIM: 193670
Orphanet: ORPHA51636
References:  5,37
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Calcium channel
References:  46,49
Tissue Distribution
Testes.
Species:  Human
Technique:  RT-PCR.
References:  21
Natural killer (NK) cells.
Species:  Human
Technique:  Flow cytometric and RNase protection assay.
References:  30
Precursor and mature megakaryocyte cells, and platelets.
Species:  Human
Technique:  RT-PCR and flow cytometry.
References:  35
CD34+ hematopoietic progenitor cells.
Species:  Human
Technique:  RT-PCR and Southern blotting.
References:  12
Fetal thymocytes.
Species:  Human
Technique:  Flow cytometry.
References:  33
Developing CNS: retina, olfactory epithelium, olfactory bulb, hippocampus, cerebellum, spinal cord.
Species:  Human
Technique:  in situ hybridisation.
References:  72
Basophils.
Species:  Human
Technique:  RT-PCR and flow cytometry.
References:  29
Blood dendritic cells.
Species:  Human
Technique:  RT-PCR.
References:  4
Microglia.
Species:  Human
Technique:  Flow cytometry.
References:  2,17
CD4 lymphocytes in normal intestinal mucosa.
Species:  Human
Technique:  Flow cytometry.
References:  3
CNS: Frontal lobe, temporal lobe, spinal cord.
Species:  Human
Technique:  Northern blotting.
References:  55
Glomerular podocytes.
Species:  Human
Technique:  RT-PCR.
References:  27
Bone marrow stromal cells (BMSCs).
Species:  Human
Technique:  Flow cytometry and RT-PCR.
References:  26
Colon.
Species:  Human
Technique:  RT-PCR and Immunohistochemistry.
References:  32
Primordial germ cells.
Species:  Mouse
Technique:  RT-PCR
References:  47
Thymus > spleen.
Species:  Mouse
Technique:  Northern blotting.
References:  22
Developing neocortex and hippocampus.
Species:  Mouse
Technique:  in situ hybridisation.
References:  42
Testicular macrophages.
Species:  Rat
Technique:  Northern blotting.
References:  21
Primary cultures of rat astrocytes and microglia.
Species:  Rat
Technique:  Northern blotting.
References:  31
Hippocampal neurons.
Species:  Rat
Technique:  RT-PCR.
References:  44
Brain: choroid plexus > olfactory nucleus, cortex, pituitary.
Species:  Rat
Technique:  Radioligand binding.
References:  6
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of chemotaxis of thymocyte cells endogenously expressing the CXCR4 receptor.
Species:  Human
Tissue:  Thymocytes.
Response measured:  Chemotaxis.
References:  69
Measurement of Ca2+ levels in thymocytes endogenously expressing the CXCR4 receptor.
Species:  Human
Tissue:  Thymocytes.
Response measured:  Stimulation of Ca2+ influx.
References:  69
Detection of HIV-1 entry into human U87MG cells transfected with human HA-tagged CXCR4 receptors and human CD4.
Species:  Human
Tissue:  Human astroglioma cell line U87MG.
Response measured:  HIV-1 entry.
References:  8
Measurement of Ca2+ levels in the human colonic epithelial cell line HT-29 endogenously expressing the CXCR4 receptor.
Species:  Human
Tissue:  HT-29 cells.
Response measured:  Increase in intracellular Ca2+ concentration.
References:  32
Detection of neutrophil morphological change (activation) by light microscopy.
Species:  Human
Tissue:  Neutrophils.
Response measured:  Activation.
References:  19
Measurement of ERK and p38 MAPK activity in HEK 293 cells transfected with the human CXCR4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Activation of ERK and p38 MAPK via β-arrestin2
References:  58
Measurement of chemotaxis of HEK 293 cells transfected with the human CXCR4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Chemotaxis involving β-arrstin2 and p38 MAPK activation.
References:  58
Measurement of Ca2+ currents in HEK 293 cells stably expressing N-type calcium channels and the rat CXCR4 receptor, using Ba2+ as the charge carrier (IBa).
Species:  Rat
Tissue:  HEK 293 cells.
Response measured:  IBa inhibition.
References:  49
Physiological Functions
HIV coreceptor.
Species:  Human
Tissue:  Intestinal cell line HT-29.
References:  13
Chemotaxis.
Species:  Human
Tissue:  Neutrophils.
References:  19
Lymphopoiesis.
Species:  Human
Tissue:  Thymocytes.
References:  33
Haematopoiesis.
Species:  Mouse
Tissue:  In vivo.
References:  72
Cell migration and survival.
Species:  Mouse
Tissue:  Primordial germ cells.
References:  47
Interneuron migration.
Species:  Mouse
Tissue:  Neocortex.
References:  57
Neovascularisation (angiogenesis).
Species:  Rat
Tissue:  Aorta.
References:  53
Physiological Consequences of Altering Gene Expression
CXCR4 receptor knockout mice exhibit abnormal development of the dorsal root ganglia with major defects in cell migration in the developing cerebellar cortex.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  42
CXCR4 receptor knockout mice exhibit defective haematopoiesis and cardiac development.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  72
CXCR4 receptor knockout mice exhibit small and malformed dorsal root ganglia as well as delayed migration of sensory neuron progenitors to the dorsal root ganglion.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  7
CXCR4 receptor knockout mice embryos exhibit defects in primordial germ cell migration and survival.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  47
CXCR4 receptor knockout mice exhibit fewer interneurons in the superficial layers of the neocortex, these interneurons instead being located in the deep layers of the neocortex.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  57
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0000260 abnormal angiogenesis PMID: 9634237 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0002144 abnormal B cell differentiation PMID: 9634237 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0002144 abnormal B cell differentiation PMID: 15520246 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0000872 abnormal cerebellum external granule cell layer morphology PMID: 9634238 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000849 abnormal cerebellum morphology PMID: 9689100 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0000849 abnormal cerebellum morphology PMID: 9634238 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0000788 abnormal cerebral cortex morphology PMID: 11983855 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0000812 abnormal dentate gyrus morphology PMID: 11983855  12183377 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0000281 abnormal interventricular septum morphology PMID: 9634238 
Cxcr4tm1Yiw|Tg(Lck-cre)1Jtak Cxcr4tm1Yiw/Cxcr4tm1Yiw,Tg(Lck-cre)1Jtak/0
Not Specified		 MGI:109563  MGI:3655253  MP:0003156 abnormal leukocyte migration PMID: 20939892 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0005460 abnormal leukopoiesis PMID: 9634238 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0002401 abnormal lymphopoiesis PMID: 9634238 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
B6.129X-Cxcr4/J		 MGI:109563  MP:0003090 abnormal muscle progenitor cell migration PMID: 16166380 
Cxcr4tm1Qma|Gab1tm1Wbm Cxcr4tm1Qma/Cxcr4tm1Qma,Gab1tm1Wbm/Gab1tm1Wbm
involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6		 MGI:108088  MGI:109563  MP:0003090 abnormal muscle progenitor cell migration PMID: 16166380 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
B6.129X-Cxcr4/J		 MGI:109563  MP:0000729 abnormal myogenesis PMID: 16166380 
Cxcr4tm1Qma|Gab1tm1Wbm Cxcr4tm1Qma/Cxcr4tm1Qma,Gab1tm1Wbm/Gab1tm1Wbm
involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6		 MGI:108088  MGI:109563  MP:0000729 abnormal myogenesis PMID: 16166380 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0002389 abnormal Peyer's patch follicle morphology PMID: 15520246 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0002982 abnormal primordial germ cell migration PMID: 12900445 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
B6.Cg-Cxcr4		 MGI:109563  MP:0002982 abnormal primordial germ cell migration PMID: 12684531 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
B6.Cg-Cxcr4		 MGI:109563  MP:0002145 abnormal T cell differentiation PMID: 12707343 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000853 absent cerebellar foliation PMID: 9689100 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0001177 atelectasis PMID: 9689100 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0004978 decreased B-1 B cell number PMID: 15520246 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0008207 decreased B-2 B cell number PMID: 15520246 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0001265 decreased body size PMID: 9689100 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000333 decreased bone marrow cell number PMID: 9689100 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
B6.Cg-Cxcr4		 MGI:109563  MP:0005092 decreased double-positive T cell number PMID: 12707343 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0004200 decreased fetal size PMID: 9634238 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0002460 decreased immunoglobulin level PMID: 15520246 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0008211 decreased mature B cell number PMID: 15520246 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0008098 decreased plasma cell number PMID: 15520246 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm1Tng|Cxcr4tm2Tng Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm1Tng/Cxcr4tm2Tng
involves: 129P2/OlaHsd * C57BL/6		 MGI:109563  MGI:88319  MP:0008098 decreased plasma cell number PMID: 15189736 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0008392 decreased primordial germ cell number PMID: 12900445 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0008208 decreased pro-B cell number PMID: 9689100 
Cxcr4tm1Yiw|Tg(Lck-cre)1Jtak Cxcr4tm1Yiw/Cxcr4tm1Yiw,Tg(Lck-cre)1Jtak/0
Not Specified		 MGI:109563  MGI:3655253  MP:0003436 decreased susceptibility to induced arthritis PMID: 20939892 
Cxcr4tm1Yiw|Tg(Lck-cre)1Jtak Cxcr4tm1Yiw/Cxcr4tm1Yiw,Tg(Lck-cre)1Jtak/0
Not Specified		 MGI:109563  MGI:3655253  MP:0000715 decreased thymocyte number PMID: 20939892 
Cxcr4tm1Qma|Gab1tm1Wbm Cxcr4tm1Qma/Cxcr4tm1Qma,Gab1tm1Wbm/Gab1tm1Wbm
involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6		 MGI:108088  MGI:109563  MP:0009907 decreased tongue size PMID: 16166380 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000885 ectopic Purkinje cell PMID: 9689100 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0001603 failure of myelopoiesis PMID: 9634237 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0000465 gastrointestinal hemorrhage PMID: 9634237 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0002192 hydrops fetalis PMID: 9634238 
Cxcr4tm1Qma|Gab1tm1Wbm Cxcr4tm1Qma/Cxcr4tm1Qma,Gab1tm1Wbm/Gab1tm1Wbm
involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6		 MGI:108088  MGI:109563  MP:0003359 hypaxial muscle hypoplasia PMID: 16166380 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0001602 impaired myelopoiesis PMID: 9689100 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0001602 impaired myelopoiesis PMID: 9634238 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000533 kidney hemorrhage PMID: 9689100 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000532 kidney vascular congestion PMID: 9689100 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0006208 lethality throughout fetal growth and development PMID: 9634238 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0002058 neonatal lethality PMID: 9634237 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0010418 perimembraneous ventricular septal defect PMID: 9634237 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0002081 perinatal lethality PMID: 9689100 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0002081 perinatal lethality PMID: 9634237 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000873 thin external granule cell layer PMID: 9689100 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Waldenstrom macroglobulinemia
Description: A malignant B-cell neoplasm characterized by lymphoplasmacytic infiltration of the bone marrow and hypersecretion of monoclonal immunoglobulin M (IgM) protein
Synonyms: lymphoplasmacytic lymphoma [Disease Ontology: DOID:0050747]
Macroglobulinemia, Waldenstrom, somatic included [OMIM: 153600]
Macroglobulinemia, Waldenstrom, susceptibility to, 1 [OMIM: 153600]
WM
Disease Ontology: DOID:0050747
OMIM: 153600
Orphanet: ORPHA33226
Comments:  Truncating mutations in the cytoplasmic tail domain of the CXCR4 gene are associated with Waldenstrom macroglobulinemia.
References:  28
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Truncation, loss of function Human S338STOP G>C 28
Truncation, loss of function Human S338STOP G>T 28
Truncation, loss of function Human S339Frameshift AGATdeleted 28
Truncation, loss of function Human S344Frameshift GAAGACTCAG>AC 28
Disease:  WHIM syndrome
Description: WHIM syndrome is an extremely rare congenital autosomal dominant immune deficiency characterized by abnormal retention of mature neutrophils in the bone marrow (myelokathexis) and occasional hypogammaglobulinemia, associated with an increased risk for bacterial infections and a susceptibility to human papillomavirus (HPV) induced lesions (cutaneous warts, genital dysplasia and invasive mucosal carcinoma) (from orphanet).
Synonyms: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM)
Warts-Infections-Leukopenia-Myelokatexis (WILM)
OMIM: 193670
Orphanet: ORPHA51636
Comments:  Truncating mutations in the cytoplasmic tail domain of the CXCR4 gene have been identified in almost all cases of WHIM syndrome. The mutations result in receptor gain of function (i.e. prolonged agonist-dependent signalling).
References:  24,28
Clinically-Relevant Mutations and Pathophysiology Comments
CXCR4 haploinsufficiency promotes hematopoietic stem cell engraftment, suggesting a useful strategy to promote hematopoietic stem cell engraftment in transplantation [43].
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Description:  An unspliced version of the human CXCR4 receptor, called CXCR4-Lo, has been found, with a 9 amino acid extension at the N-terminus. This receptor may be a functional backup to CXCR4 during embryogenesis.
References:  20
Type:  Splice variant
Species:  Mouse
Description:  A fully functioning splice variant of the mouse CXCR4 receptor, CXCR4-B, has been found with a different expression pattern from CXCR4.
References:  23,46
General Comments
CXCR4 is a receptor for stromal cell-derived factor-1 (SDF1; CXCL12) [9,48]. When co-expressed alongside CD4, CXCR4 is involved in HIV-1 infection. It is the major T cell-tropic coreceptor for HIV-1. In contrast, CCR5 serves as the principal macrophage-tropic coreceptor for viral entry. SDF1 inhibits HIV-1 infection by lymphocyte-tropic HIV-1 strains [9,48].

Cancer cells overexpress CXCR4 when compared to normal cells, and it is the most common chemokine receptor found on cancer cells. Its ligand CXCL12 is also found in the tumour micorenvironment [45]. Expression of CXCR4 correlates with cancer cell metastasis, angiogenesis, and tumour growth [10]. CXCR4 antagonists are predicted to exhibit anti-tumour activity via inhibition of CXCL12-CXCR4-mediated pro-survival signaling and chemotaxis [45,63].

References

Show »

1. Adlere I, Sun S, Zarca A, Roumen L, Gozelle M, Perpina CV, Caspar B, Arimont M, Bebelman JP, Briddon SJ et al.. (2018) Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists. European Journal of Medicinal Chemistry, 162: 631-649. DOI: 10.1016/j.ejmech.2018.10.060

2. Albright AV, Shieh JT, Itoh T, Lee B, Pleasure D, O'Connor MJ, Doms RW, González-Scarano F. (1999) Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates. J. Virol., 73 (1): 205-13. [PMID:9847323]

3. Anton PA, Elliott J, Poles MA, McGowan IM, Matud J, Hultin LE, Grovit-Ferbas K, Mackay CR, Chen ISY, Giorgi JV. (2000) Enhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue. AIDS, 14 (12): 1761-5. [PMID:10985313]

4. 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]

5. Balabanian K, Lagane B, Pablos JL, Laurent L, Planchenault T, Verola O, Lebbe C, Kerob D, Dupuy A, Hermine O et al.. (2005) WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12. Blood, 105 (6): 2449-57. [PMID:15536153]

6. Banisadr G, Dicou E, Berbar T, Rostène W, Lombet A, Haour F. (2000) Characterization and visualization of [125I] stromal cell-derived factor-1alpha binding to CXCR4 receptors in rat brain and human neuroblastoma cells. J. Neuroimmunol., 110 (1-2): 151-60. [PMID:11024545]

7. Belmadani A, Tran PB, Ren D, Assimacopoulos S, Grove EA, Miller RJ. (2005) The chemokine stromal cell-derived factor-1 regulates the migration of sensory neuron progenitors. J. Neurosci., 25 (16): 3995-4003. [PMID:15843601]

8. Berson JF, Long D, Doranz BJ, Rucker J, Jirik FR, Doms RW. (1996) A seven-transmembrane domain receptor involved in fusion and entry of T-cell-tropic human immunodeficiency virus type 1 strains. J. Virol., 70 (9): 6288-95. [PMID:8709256]

9. Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, Springer TA. (1996) The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature, 382 (6594): 829-33. [PMID:8752280]

10. Burger JA, Kipps TJ. (2006) CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood, 107 (5): 1761-7. [PMID:16269611]

11. Crump MP, Gong JH, Loetscher P, Rajarathnam K, Amara A, Arenzana-Seisdedos F, Virelizier JL, Baggiolini M, Sykes BD, Clark-Lewis I. (1997) Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO J., 16 (23): 6996-7007. [PMID:9384579]

12. Deichmann M, Kronenwett R, Haas R. (1997) Expression of the human immunodeficiency virus type-1 coreceptors CXCR-4 (fusin, LESTR) and CKR-5 in CD34+ hematopoietic progenitor cells. Blood, 89 (10): 3522-8. [PMID:9160656]

13. Delézay O, Koch N, Yahi N, Hammache D, Tourres C, Tamalet C, Fantini J. (1997) Co-expression of CXCR4/fusin and galactosylceramide in the human intestinal epithelial cell line HT-29. AIDS, 11 (11): 1311-8. [PMID:9302439]

14. Di Salvo J, Koch GE, Johnson KE, Blake AD, Daugherty BL, DeMartino JA, Sirotina-Meisher A, Liu Y, Springer MS, Cascieri MA et al.. (2000) The CXCR4 agonist ligand stromal derived factor-1 maintains high affinity for receptors in both Galpha(i)-coupled and uncoupled states. Eur. J. Pharmacol., 409 (2): 143-54. [PMID:11104827]

15. Drury LJ, Ziarek JJ, Gravel S, Veldkamp CT, Takekoshi T, Hwang ST, Heveker N, Volkman BF, Dwinell MB. (2011) Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways. Proc. Natl. Acad. Sci. U.S.A., 108 (43): 17655-60. [PMID:21990345]

16. Feng Y, Broder CC, Kennedy PE, Berger EA. (1996) HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science, 272 (5263): 872-7. [PMID:8629022]

17. 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]

18. Foley M, Pow A, Griffiths K, Cobb S, Viduka K. (2016) Cxcr4 binding molecules. Patent number: WO2016109872. Assignee: Adalta Pty Ltd. Priority date: 09/01/2015. Publication date: 14/07/2016.

19. Gouwy M, Struyf S, Catusse J, Proost P, Van Damme J. (2004) Synergy between proinflammatory ligands of G protein-coupled receptors in neutrophil activation and migration. J. Leukoc. Biol., 76 (1): 185-94. [PMID:15075362]

20. Gupta SK, Pillarisetti K. (1999) Cutting edge: CXCR4-Lo: molecular cloning and functional expression of a novel human CXCR4 splice variant. J. Immunol., 163 (5): 2368-72. [PMID:10452968]

21. Habasque C, Aubry F, Jégou B, Samson M. (2002) Study of the HIV-1 receptors CD4, CXCR4, CCR5 and CCR3 in the human and rat testis. Mol. Hum. Reprod., 8 (5): 419-25. [PMID:11994538]

22. Heesen M, Berman MA, Benson JD, Gerard C, Dorf ME. (1996) Cloning of the mouse fusin gene, homologue to a human HIV-1 co-factor. J. Immunol., 157 (12): 5455-60. [PMID:8955194]

23. Heesen M, Berman MA, Höpken UE, Gerard NP, Dorf ME. (1997) Alternate splicing of mouse fusin/CXC chemokine receptor-4: stromal cell-derived factor-1alpha is a ligand for both CXC chemokine receptor-4 isoforms. J. Immunol., 158 (8): 3561-4. [PMID:9103415]

24. Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, Klotman ME, Diaz GA. (2003) Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat. Genet., 34 (1): 70-4. [PMID:12692554]

25. Hesselgesser J, Liang M, Hoxie J, Greenberg M, Brass LF, Orsini MJ, Taub D, Horuk R. (1998) Identification and characterization of the CXCR4 chemokine receptor in human T cell lines: ligand binding, biological activity, and HIV-1 infectivity. J. Immunol., 160 (2): 877-83. [PMID:9551924]

26. Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. (2006) Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells, 24 (4): 1030-41. [PMID:16253981]

27. 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]

28. Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Manning RJ, Tripsas C, Patterson CJ, Sheehy P et al.. (2014) The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood, 123 (11): 1637-46. [PMID:24366360]

29. Iikura M, Miyamasu M, Yamaguchi M, Kawasaki H, Matsushima K, Kitaura M, Morita Y, Yoshie O, Yamamoto K, Hirai K. (2001) Chemokine receptors in human basophils: inducible expression of functional CXCR4. J Leukoc Biol, 70: 113-120. [PMID:11435493]

30. Inngjerdingen M, Damaj B, Maghazachi AA. (2001) Expression and regulation of chemokine receptors in human natural killer cells. Blood, 97 (2): 367-75. [PMID:11154210]

31. Jiang Y, Salafranca MN, Adhikari S, Xia Y, Feng L, Sonntag MK, deFiebre CM, Pennell NA, Streit WJ, Harrison JK. (1998) Chemokine receptor expression in cultured glia and rat experimental allergic encephalomyelitis. J. Neuroimmunol., 86 (1): 1-12. [PMID:9655467]

32. Jordan NJ, Kolios G, Abbot SE, Sinai MA, Thompson DA, Petraki K, Westwick J. (1999) Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells. J. Clin. Invest., 104 (8): 1061-9. [PMID:10525044]

33. Kitchen SG, Zack JA. (1997) CXCR4 expression during lymphopoiesis: implications for human immunodeficiency virus type 1 infection of the thymus. J. Virol., 71 (9): 6928-34. [PMID:9261420]

34. Kledal TN, Rosenkilde MM, Coulin F, Simmons G, Johnsen AH, Alouani S, Power CA, Lüttichau HR, Gerstoft J, Clapham PR et al.. (1997) A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science, 277 (5332): 1656-9. [PMID:9287217]

35. Kowalska MA, Ratajczak J, Hoxie J, Brass LF, Gewirtz A, Poncz M, Ratajczak MZ. (1999) Megakaryocyte precursors, megakaryocytes and platelets express the HIV co-receptor CXCR4 on their surface: determination of response to stromal-derived factor-1 by megakaryocytes and platelets. Br. J. Haematol., 104 (2): 220-9. [PMID:10050701]

36. Kuhne M, Brams P,Tanamachi DM,Korman AJ, Cardarelli JM. (2013) Human monoclonal antibodies that bind CXCR4. Patent number: US8450464 B2. Assignee: Medarex, Inc.. Priority date: 02/10/2006. Publication date: 28/05/2013.

37. Lagane B, Chow KY, Balabanian K, Levoye A, Harriague J, Planchenault T, Baleux F, Gunera-Saad N, Arenzana-Seisdedos F, Bachelerie F. (2008) CXCR4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome. Blood, 112 (1): 34-44. [PMID:18436740]

38. Larochelle A, Krouse A, Metzger M, Orlic D, Donahue RE, Fricker S, Bridger G, Dunbar CE, Hematti P. (2006) AMD3100 mobilizes hematopoietic stem cells with long-term repopulating capacity in nonhuman primates. Blood, 107 (9): 3772-8. [PMID:16439684]

39. Liu X, Mao J, Han C, Peng S, Li C, Jin T, Fan C, Shan Z, Teng W. (2016) CXCR4 antagonist AMD3100 ameliorates thyroid damage in autoimmune thyroiditis in NOD.H‑2h⁴ mice. Mol Med Rep, 13 (4): 3604-12. [PMID:26935473]

40. Loetscher M, Geiser T, O'Reilly T, Zwahlen R, Baggiolini M, Moser B. (1994) Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. J. Biol. Chem., 269 (1): 232-7. [PMID:8276799]

41. Loetscher P, Gong JH, Dewald B, Baggiolini M, Clark-Lewis I. (1998) N-terminal peptides of stromal cell-derived factor-1 with CXC chemokine receptor 4 agonist and antagonist activities. J. Biol. Chem., 273 (35): 22279-83. [PMID:9712844]

42. Lu M, Grove EA, Miller RJ. (2002) Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc. Natl. Acad. Sci. U.S.A., 99 (10): 7090-5. [PMID:11983855]

43. McDermott DH, Gao JL, Liu Q, Siwicki M, Martens C, Jacobs P, Velez D, Yim E, Bryke CR, Hsu N et al.. (2015) Chromothriptic cure of WHIM syndrome. Cell, 160 (4): 686-99. [PMID:25662009]

44. 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. U.S.A., 95 (24): 14500-5. [PMID:9826729]

45. Miller EJ, Jecs E, Truax VM, Katzman BM, Tahirovic YA, Wilson RJ, Kuo KM, Kim MB, Nguyen HH, Saindane MT et al.. (2018) Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties. J. Med. Chem., 61 (3): 946-979. [PMID:29350534]

46. Moepps B, Frodl R, Rodewald HR, Baggiolini M, Gierschik P. (1997) Two murine homologues of the human chemokine receptor CXCR4 mediating stromal cell-derived factor 1alpha activation of Gi2 are differentially expressed in vivo. Eur. J. Immunol., 27 (8): 2102-12. [PMID:9295051]

47. Molyneaux KA, Zinszner H, Kunwar PS, Schaible K, Stebler J, Sunshine MJ, O'Brien W, Raz E, Littman D, Wylie C et al.. (2003) The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development, 130 (18): 4279-86. [PMID:12900445]

48. Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF et al.. (1996) The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature, 382 (6594): 833-5. [PMID:8752281]

49. 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]

50. Pozzobon T, Goldoni G, Viola A, Molon B. (2016) CXCR4 signaling in health and disease. Immunol. Lett., 177: 6-15. [PMID:27363619]

51. Randhawa S, Cho BS, Ghosh D, Sivina M, Koehrer S, Müschen M, Peled A, Davis RE, Konopleva M, Burger JA. (2016) Effects of pharmacological and genetic disruption of CXCR4 chemokine receptor function in B-cell acute lymphoblastic leukaemia. Br. J. Haematol., 174 (3): 425-36. [PMID:27071778]

52. Rueda P, Balabanian K, Lagane B, Staropoli I, Chow K, Levoye A, Laguri C, Sadir R, Delaunay T, Izquierdo E et al.. (2008) The CXCL12gamma chemokine displays unprecedented structural and functional properties that make it a paradigm of chemoattractant proteins. PLoS ONE, 3 (7): e2543. [PMID:18648536]

53. Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, Anver MR, Kleinman HK, Murphy WJ, Oppenheim JJ. (1999) Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha. Am. J. Pathol., 154 (4): 1125-35. [PMID:10233851]

54. Scala S. (2015) Molecular Pathways: Targeting the CXCR4-CXCL12 Axis--Untapped Potential in the Tumor Microenvironment. Clin. Cancer Res., 21 (19): 4278-85. [PMID:26199389]

55. Sehgal A, Ricks S, Boynton AL, Warrick J, Murphy GP. (1998) Molecular characterization of CXCR-4: a potential brain tumor-associated gene. J Surg Oncol, 69 (4): 239-48. [PMID:9881942]

56. Skerlj RT, Bridger GJ, Kaller A, McEachern EJ, Crawford JB, Zhou Y, Atsma B, Langille J, Nan S, Veale D et al.. (2010) Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication. J. Med. Chem., 53 (8): 3376-88. [PMID:20297846]

57. Stumm RK, Zhou C, Ara T, Lazarini F, Dubois-Dalcq M, Nagasawa T, Höllt V, Schulz S. (2003) CXCR4 regulates interneuron migration in the developing neocortex. J. Neurosci., 23 (12): 5123-30. [PMID:12832536]

58. Sun Y, Cheng Z, Ma L, Pei G. (2002) Beta-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation. J. Biol. Chem., 277 (51): 49212-9. [PMID:12370187]

59. Tamamura H, Xu Y, Hattori T, Zhang X, Arakaki R, Kanbara K, Omagari A, Otaka A, Ibuka T, Yamamoto N et al.. (1998) A low-molecular-weight inhibitor against the chemokine receptor CXCR4: a strong anti-HIV peptide T140. Biochem. Biophys. Res. Commun., 253 (3): 877-82. [PMID:9918823]

60. Thoma G, Streiff MB, Kovarik J, Glickman F, Wagner T, Beerli C, Zerwes HG. (2008) Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo. J. Med. Chem., 51 (24): 7915-20. [PMID:19053768]

61. Walenkamp AME, Lapa C, Herrmann K, Wester HJ. (2017) CXCR4 Ligands: The Next Big Hit?. J. Nucl. Med., 58 (Suppl 2): 77S-82S. [PMID:28864616]

62. Wang Z, Sun J, Feng Y, Tian X, Wang B, Zhou Y. (2016) Oncogenic roles and drug target of CXCR4/CXCL12 axis in lung cancer and cancer stem cell. Tumour Biol., 37 (7): 8515-28. [PMID:27079871]

63. Wilson RJ, Jecs E, Miller EJ, Nguyen HH, Tahirovic YA, Truax VM, Kim MB, Kuo KM, Wang T, Sum CS et al.. (2018) Synthesis and SAR of 1,2,3,4-Tetrahydroisoquinoline-Based CXCR4 Antagonists. ACS Med Chem Lett, 9 (1): 17-22. [PMID:29348805]

64. Wong ML, Xin WW, Duman RS. (1996) Rat LCR1: cloning and cellular distribution of a putative chemokine receptor in brain. Mol. Psychiatry, 1 (2): 133-40. [PMID:9118323]

65. Wong RS, Bodart V, Metz M, Labrecque J, Bridger G, Fricker SP. (2008) Comparison of the potential multiple binding modes of bicyclam, monocylam, and noncyclam small-molecule CXC chemokine receptor 4 inhibitors. Mol. Pharmacol., 74 (6): 1485-95. [PMID:18768385]

66. Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC et al.. (2010) Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science, 330 (6007): 1066-71. [PMID:20929726]

67. Wu KJ, Yu SJ, Shia KS, Wu CH, Song JS, Kuan HH, Yeh KC, Chen CT, Bae E, Wang Y. (2017) A Novel CXCR4 Antagonist CX549 Induces Neuroprotection in Stroke Brain. Cell Transplant, 26 (4): 571-583. [PMID:27938478]

68. Yu L, Cecil J, Peng SB, Schrementi J, Kovacevic S, Paul D, Su EW, Wang J. (2006) Identification and expression of novel isoforms of human stromal cell-derived factor 1. Gene, 374: 174-9. [PMID:16626895]

69. Zamarchi R, Allavena P, Borsetti A, Stievano L, Tosello V, Marcato N, Esposito G, Roni V, Paganin C, Bianchi G et al.. (2002) Expression and functional activity of CXCR-4 and CCR-5 chemokine receptors in human thymocytes. Clin. Exp. Immunol., 127 (2): 321-30. [PMID:11876757]

70. Zhang H, Kang D, Huang B, Liu N, Zhao F, Zhan P, Liu X. (2016) Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities. Eur J Med Chem, 114: 65-78. [PMID:26974376]

71. Zhang WB, Navenot JM, Haribabu B, Tamamura H, Hiramatu K, Omagari A, Pei G, Manfredi JP, Fujii N, Broach JR, Peiper SC. (2002) A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists. J Biol Chem, 277: 24515-24521. [PMID:11923301]

72. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR. (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature, 393 (6685): 595-9. [PMID:9634238]

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