Target General Infomation
Target ID
T96079 (Former ID: TTDC00121)
Target Name
C-X-C chemokine receptor type 4 (CXCR4)
Synonyms
Stromal cell-derived factor 1 receptor; SDF-1 receptor; NPYRL; Lipopolysaccharide-associated protein 3; Leukocyte-derived seven transmembrane domain receptor; LPS-associated protein 3; LESTR; LCR1; LAP-3; HM89; Fusin; FB22; Chemokine receptor CXCR4; CXCR-4; CXC-R4; CD184 antigen; CD184
Gene Name
CXCR4
Target Type
Successful target
[1]
Disease [+] 1 Target-related Diseases +
1 Malignant haematopoietic neoplasm [ICD-11: 2B33]
Function
Involved in the AKT signaling cascade. Plays a role in regulation of cell migration, e. g. during wound healing. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes. Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival. Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation.
BioChemical Class
GPCR rhodopsin
UniProt ID
CXCR4_HUMAN
Sequence
MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSIIFLTGIVGNGLVI
LVMGYQKKLRSMTDKYRLHLSVADLLFVITLPFWAVDAVANWYFGNFLCKAVHVIYTVNL
YSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKVVYVGVWIPALLLTIPDFIFANVSEA
DDRYICDRFYPNDLWVVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKT
TVILILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPI
LYAFLGAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS
Drugs and Modes of Action
Approved Drug(s) [+] 1 Approved Drugs +
1 Plerixafor Drug Info Approved Non-hodgkin lymphoma [1], [2], [3]
Clinical Trial Drug(s) [+] 15 Clinical Trial Drugs +
1 BL-8040 Drug Info Phase 3 Multiple myeloma [4]
2 Balixafortide Drug Info Phase 2 Breast cancer [5]
3 POL-6326 Drug Info Phase 2 Human immunodeficiency virus infection [6]
4 TG-0054 Drug Info Phase 2 Macular degeneration [7]
5 AMD-070 Drug Info Phase 1/2 Human immunodeficiency virus infection [8], [9]
6 CTCE-9908 Drug Info Phase 1/2 Sarcoma [10]
7 Ulocuplumab Drug Info Phase 1/2 Haematological malignancy [11]
8 USL311 Drug Info Phase 1/2 Recurring respiratory infection [4]
9 ALX-0651 Drug Info Phase 1 Haematological malignancy [12]
10 BMS-936564 Drug Info Phase 1 B-cell chronic lymphocytic leukaemia [13]
11 CTCE-0214 Drug Info Phase 1 Constitutional neutropenia [14]
12 GMI-1359 Drug Info Phase 1 Solid tumour/cancer [4]
13 LY-2624587 Drug Info Phase 1 Solid tumour/cancer [15]
14 MSX-122 Drug Info Phase 1 Solid tumour/cancer [16]
15 PF-06747143 Drug Info Phase 1 Acute myeloid leukaemia [17]
Discontinued Drug(s) [+] 3 Discontinued Drugs +
1 Garnocestim Drug Info Discontinued in Phase 1 Bone marrow transplantation [18]
2 SURADISTA Drug Info Discontinued in Phase 1 Solid tumour/cancer [19]
3 KRH-2731 Drug Info Terminated Human immunodeficiency virus infection [20]
Mode of Action [+] 5 Modes of Action +
Antagonist [+] 18 Antagonist drugs +
1 Plerixafor Drug Info [1]
2 Balixafortide Drug Info [5]
3 BL-8040 Drug Info [21]
4 POL-6326 Drug Info [22]
5 AMD-070 Drug Info [24], [25]
6 Ulocuplumab Drug Info [17], [26]
7 USL311 Drug Info [4]
8 MSX-122 Drug Info [30]
9 PF-06747143 Drug Info [17]
10 AT-009 Drug Info [34]
11 GSK-812397 Drug Info [34]
12 isothiourea-1a Drug Info [38]
13 isothiourea-1t Drug Info [38]
14 LP-0067 Drug Info [34]
15 T134 Drug Info [39]
16 T140 Drug Info [39]
17 T22 Drug Info [39]
18 viral macrophage inflammatory protein-II Drug Info [41]
Inhibitor [+] 28 Inhibitor drugs +
1 TG-0054 Drug Info [23]
2 ALX-0651 Drug Info [27]
3 GMI-1359 Drug Info [4]
4 Cyclo(-D-Ala-D-Arg-L-Arg-L-Nal-Gly-) Drug Info [36]
5 Cyclo(-D-MeTyr-D-Arg-L-Arg-L-Nal-Gly-) Drug Info [36]
6 Cyclo(-D-MeTyr-L-Arg-L-Arg-L-Nal-Gly-) Drug Info [36]
7 Cyclo(-D-Tyr-Arg-Arg-Nal-Gly-) Drug Info [37]
8 Cyclo(-D-Tyr-D-Ala-L-Arg-L-Nal-Gly-) Drug Info [36]
9 Cyclo(-D-Tyr-D-Arg-L-Arg-L-MeNal-Gly-) Drug Info [36]
10 Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-beta-Ala-) Drug Info [36]
11 Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-D-Ala-) Drug Info [36]
12 Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-Gly-) Drug Info [36]
13 Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-L-Ala-) Drug Info [36]
14 Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-L-Pic-) Drug Info [36]
15 Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-Sar-) Drug Info [36]
16 Cyclo(-D-Tyr-D-Arg-L-MeArg-L-Nal-Gly-) Drug Info [36]
17 Cyclo(-D-Tyr-D-MeArg-L-Arg-L-Nal-Gly-) Drug Info [36]
18 Cyclo(-D-Tyr-L-Ala-L-Arg-L-Nal-Gly-) Drug Info [36]
19 Cyclo(-D-Tyr-L-Arg-L-Arg-L-Ala-Sar-) Drug Info [36]
20 Cyclo(-D-Tyr-L-Arg-L-Arg-L-MeNal-Gly-) Drug Info [36]
21 Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-beta-Ala-) Drug Info [36]
22 Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-D-Ala-) Drug Info [36]
23 Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-Gly-) Drug Info [36]
24 Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-L-Ala-) Drug Info [36]
25 Cyclo(-D-Tyr-L-Arg-L-MeArg-L-Nal-Gly-) Drug Info [36]
26 Cyclo(-D-Tyr-L-MeArg-L-Arg-L-Nal-Gly-) Drug Info [36]
27 ND-401 Drug Info [34]
28 TN-14003 Drug Info [40]
Modulator [+] 8 Modulator drugs +
1 CTCE-9908 Drug Info [10]
2 BMS-936564 Drug Info [28]
3 Garnocestim Drug Info [31]
4 SURADISTA Drug Info [32]
5 CTCE-0324 Drug Info [34]
6 CXCR4 gene disrupted T cells Drug Info [34]
7 KUR-CXCR4 Drug Info [34]
8 NB-325 Drug Info [34]
Agonist [+] 3 Agonist drugs +
1 CTCE-0214 Drug Info [29]
2 ATI-2341 Drug Info [34]
3 CXCL8 Drug Info [35]
Binder [+] 1 Binder drugs +
1 KRH-2731 Drug Info [33]
Target Regulators
Target-regulating microRNAs
Target-regulating Transcription Factors
Target-interacting Proteins
Target Profiles in Patients
Target Expression
 Profile (TEP)
Target Affiliated Biological Pathways
KEGG Pathway [+] 7 KEGG Pathways +
1 Cytokine-cytokine receptor interaction
2 Chemokine signaling pathway
3 Endocytosis
4 Axon guidance
5 Leukocyte transendothelial migration
6 Intestinal immune network for IgA production
7 Pathways in cancer
NetPath Pathway [+] 3 NetPath Pathways +
1 IL2 Signaling Pathway
2 IL4 Signaling Pathway
3 Leptin Signaling Pathway
Panther Pathway [+] 2 Panther Pathways +
1 Axon guidance mediated by Slit/Robo
2 Inflammation mediated by chemokine and cytokine signaling pathway
PID Pathway [+] 5 PID Pathways +
1 S1P3 pathway
2 CXCR4-mediated signaling events
3 Syndecan-4-mediated signaling events
4 HIF-1-alpha transcription factor network
5 Ephrin B reverse signaling
Reactome [+] 3 Reactome Pathways +
1 Binding and entry of HIV virion
2 Chemokine receptors bind chemokines
3 G alpha (i) signalling events
WikiPathways [+] 7 WikiPathways +
1 GPCRs, Class A Rhodopsin-like
2 Hematopoietic Stem Cell Differentiation
3 HIV Life Cycle
4 Cardiac Progenitor Differentiation
5 Peptide GPCRs
6 GPCR ligand binding
7 GPCR downstream signaling
Target-Related Models and Studies
Target Validation
References
REF 1 Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
REF 2 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: 844).
REF 3 2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.
REF 4 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 5 Anti-ageing pipeline starts to mature.Nat Rev Drug Discov. 2018 Sep;17(9):609-612.
REF 6 ClinicalTrials.gov (NCT01105403) Exploratory Study on POL6326 in Stem Cell Mobilization. U.S. National Institutes of Health.
REF 7 ClinicalTrials.gov (NCT01018979) Safety and PK/PD of TG-0054 in Multiple Myeloma, Non-Hodgkin Lymphoma and Hodgkin Disease Patients. U.S. National Institutes of Health.
REF 8 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: 8580).
REF 9 ClinicalTrials.gov (NCT00089466) Safety and Activity of the Oral HIV Entry Inhibitor AMD11070 in HIV Infected Patients. U.S. National Institutes of Health.
REF 10 A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer. J Surg Res. 2009 Aug;155(2):231-6.
REF 11 ClinicalTrials.gov (NCT02472977) Safety and Efficacy Study of Ulocuplumab and Nivolumab in Subjects With Solid Tumors.
REF 12 ClinicalTrials.gov (NCT01374503) First in Man Study of ALX-0651, a Nanobody Inhibiting CXCR4. U.S. National Institutes of Health.
REF 13 ClinicalTrials.gov (NCT02305563) Phase 1 Study of BMS-936564. U.S. National Institutes of Health.
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 800021975)
REF 15 ClinicalTrials.gov (NCT01139788) A Study of LY2624587 in Patients With Advanced Cancer. U.S. National Institutes of Health.
REF 16 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027582)
REF 17 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
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 800010770)
REF 19 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004409)
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 800020279)
REF 21 The CXCR4 Antagonist BL-8040 Efficiently Induces Apoptosis and Inhibits The Survival Of AML Cells. November 15, 2013; Blood: 122 (21).
REF 22 CXCR4 inhibitors: tumor vasculature and therapeutic challenges. Recent Pat Anticancer Drug Discov. 2012 Sep;7(3):251-64.
REF 23 CXCR4 Antagonist TG-0054 Mobilizes Mesenchymal Stem Cells, Attenuates Inflammation, and Preserves Cardiac Systolic Function in a Porcine Model of Myocardial Infarction. Cell Transplant. 2015;24(7):1313-28.
REF 24 Pharmacokinetic effect of AMD070, an Oral CXCR4 antagonist, on CYP3A4 and CYP2D6 substrates midazolam and dextromethorphan in healthy volunteers. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):559-65.
REF 25 Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers. Antimicrob Agents Chemother. 2008 May;52(5):1630-4.
REF 26 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 27 Therapeutic antibodies directed at G protein-coupled receptors. MAbs. 2010 Nov-Dec; 2(6): 594-606.
REF 28 BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin Cancer Res. 2013 Jan 15;19(2):357-66.
REF 29 Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation. Inflammation. 2012 Feb;35(1):130-7.
REF 30 Comparative evaluation of CC chemokine-induced migration of murine CD8alpha+ and CD8alpha- dendritic cells and their in vivo trafficking. J Leukoc Biol. 2004 Feb;75(2):275-85.
REF 31 CN patent application no. 101094684, With the combination of chemokine activation progenitor cells/stem cells.
REF 32 Suradista NSC 651016 inhibits the angiogenic activity of CXCL12-stromal cell-derived factor 1alpha. Clin Cancer Res. 2002 Dec;8(12):3955-60.
REF 33 Progress in targeting HIV-1 entry. Drug Discov Today. 2005 Aug 15;10(16):1085-94.
REF 34 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: 71).
REF 35 Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11791-6.
REF 36 Structure-activity relationships of cyclic peptide-based chemokine receptor CXCR4 antagonists: disclosing the importance of side-chain and backbone... J Med Chem. 2007 Jan 25;50(2):192-8.
REF 37 Identification of novel non-peptide CXCR4 antagonists by ligand-based design approach. Bioorg Med Chem Lett. 2008 Jul 15;18(14):4124-9.
REF 38 Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo. J Med Chem. 2008 Dec 25;51(24):7915-20.
REF 39 A low-molecular-weight inhibitor against the chemokine receptor CXCR4: a strong anti-HIV peptide T140. Biochem Biophys Res Commun. 1998 Dec 30;253(3):877-82.
REF 40 Discovery of small molecule CXCR4 antagonists. J Med Chem. 2007 Nov 15;50(23):5655-64.
REF 41 A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science. 1997 Sep 12;277(5332):1656-9.

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