Target Information

Target General Infomation
Target ID
T96079
Former ID
TTDC00121
Target Name
C-X-C chemokine receptor 4
Gene Name
CXCR4
Synonyms
CD184 antigen; CXC-R4; CXCR-4; Chemokine receptor CXCR4; FB22; Fusin; HM89; LCR1; LESTR; Leukocyte-derived seven transmembrane domain receptor; NPYRL; SDF-1 receptor; Stromal cell-derived factor 1 receptor; CXCR4
Target Type
Successful
Disease Autoimmune diabetes [ICD10: E08-E13]
Acute myeloid leukemia [ICD9: 205; ICD10: C92.0]
Acute lymphoblastic leukemia [ICD9: 204.0, 556; ICD10: C91.0]
Acute myeloid leukemia; B-cell chronic lymphocytic leukemia [ICD9: 202.8, 203.0, 204.1, 205.0, 208.9; ICD10: C81-C86, C90.0, C91-C95, C91.1, C92.0]
Bone marrow transplantation [ICD9: 279.5, 996; ICD10: D89.8, T86]
Cancer [ICD9: 140-229; ICD10: C00-C96]
HIV-1 infection [ICD9: 001-139, 042; ICD10: B20-B24]
Human immunodeficiency virus infection [ICD9: 279.3; ICD10: B20-B26]
Human immunodeficiency virus infection; Non-hodgkin's lymphoma; Late-stage solid tumors [ICD9:279.3, 140-199, 200, 202, 202.8, 210-229; ICD10: B20-B26, C00-C75, C7A, C7B, C81-C86, C82-C85, D10-D36, D3A]
Hematological malignancies [ICD9: 200-209; ICD10: C81-C86]
Hematopoietic [ICD10: D50-D89]
Macular degeneration [ICD9: 362.5; ICD10: H35.3]
Peripheral vascular disease [ICD9: 443.9; ICD10: I73.9]
Sarcoma [ICD9: 202.8; ICD10: C81-C86]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
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. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. 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. Acts as a coreceptor (CD4 being the primary receptor) for HIV-1 X4 isolates and as a primary receptor for some HIV-2 isolates. Promotes Env-mediated fusion of the virus. Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes.
BioChemical Class
GPCR rhodopsin
Target Validation
T96079
UniProt ID
P61073
Sequence
MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSIIFLTGIVGNGLVI
LVMGYQKKLRSMTDKYRLHLSVADLLFVITLPFWAVDAVANWYFGNFLCKAVHVIYTVNL
YSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKVVYVGVWIPALLLTIPDFIFANVSEA
DDRYICDRFYPNDLWVVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKT
TVILILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPI
LYAFLGAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS
Structure
1ILP; 1ILQ; 2LNL; 2K03; 2K04; 2K05; 3ODU; 3OE0; 3OE6; 3OE8; 3OE9
Drugs and Mode of Action
Drug(s) Plerixafor Drug Info Approved Human immunodeficiency virus infection; Non-hodgkin's lymphoma; Late-stage solid tumors [529941], [537114], [543136]
BL-8040 Drug Info Phase 2 Acute myeloid leukemia [525271]
POL-6326 Drug Info Phase 2 Human immunodeficiency virus infection [523007]
TG-0054 Drug Info Phase 2 Macular degeneration [522865]
AMD-070 Drug Info Phase 1/2 Human immunodeficiency virus infection [521607], [543204]
CTCE-9908 Drug Info Phase 1/2 Sarcoma [530179]
ALX-0651 Drug Info Phase 1 Hematological malignancies [523519]
BMS-936564 Drug Info Phase 1 Acute myeloid leukemia; B-cell chronic lymphocytic leukemia [525014]
CTCE-0214 Drug Info Phase 1 Hematopoietic [548105]
LY-2624587 Drug Info Phase 1 Cancer [523067]
MSX-122 Drug Info Phase 1 Solid tumours [548672]
Garnocestim Drug Info Discontinued in Phase 1 Bone marrow transplantation [546869]
SURADISTA Drug Info Discontinued in Phase 1 Solid tumours [545728]
KRH-2731 Drug Info Terminated Human immunodeficiency virus infection [547903]
Inhibitor ALX-0651 Drug Info [544156]
Cyclo(-D-Ala-D-Arg-L-Arg-L-Nal-Gly-) Drug Info [528618]
Cyclo(-D-MeTyr-D-Arg-L-Arg-L-Nal-Gly-) Drug Info [528618]
Cyclo(-D-MeTyr-L-Arg-L-Arg-L-Nal-Gly-) Drug Info [528618]
Cyclo(-D-Tyr-Arg-Arg-Nal-Gly-) Drug Info [529526]
Cyclo(-D-Tyr-D-Ala-L-Arg-L-Nal-Gly-) Drug Info [528618]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-MeNal-Gly-) Drug Info [528618]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-beta-Ala-) Drug Info [528618]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-D-Ala-) Drug Info [528618]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-Gly-) Drug Info [528618]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-L-Ala-) Drug Info [528618]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-L-Pic-) Drug Info [528618]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-Sar-) Drug Info [528618]
Cyclo(-D-Tyr-D-Arg-L-MeArg-L-Nal-Gly-) Drug Info [528618]
Cyclo(-D-Tyr-D-MeArg-L-Arg-L-Nal-Gly-) Drug Info [528618]
Cyclo(-D-Tyr-L-Ala-L-Arg-L-Nal-Gly-) Drug Info [528618]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-Ala-Sar-) Drug Info [528618]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-MeNal-Gly-) Drug Info [528618]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-beta-Ala-) Drug Info [528618]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-D-Ala-) Drug Info [528618]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-Gly-) Drug Info [528618]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-L-Ala-) Drug Info [528618]
Cyclo(-D-Tyr-L-Arg-L-MeArg-L-Nal-Gly-) Drug Info [528618]
Cyclo(-D-Tyr-L-MeArg-L-Arg-L-Nal-Gly-) Drug Info [528618]
ND-401 Drug Info [543930]
TG-0054 Drug Info [532779]
TN-14003 Drug Info [529115]
Antagonist AMD-070 Drug Info [536630], [536663]
AT-009 Drug Info [543930]
BL-8040 Drug Info [550382]
GSK-812397 Drug Info [543930]
isothiourea-1a Drug Info [529840]
isothiourea-1t Drug Info [529840]
LP-0067 Drug Info [543930]
MSX-122 Drug Info [535860]
Plerixafor Drug Info [537114]
POL-6326 Drug Info [531821]
T134 Drug Info [534819]
T140 Drug Info [534819]
T22 Drug Info [534819]
viral macrophage inflammatory protein-II Drug Info [534456]
Agonist ATI-2341 Drug Info [543930]
CTCE-0214 Drug Info [531347]
CXCL8 Drug Info [527153]
Modulator BMS-936564 Drug Info [532141]
CTCE-0324 Drug Info [543930]
CTCE-9908 Drug Info [530179]
CXCR4 gene disrupted T cells Drug Info [543930]
Garnocestim Drug Info [551900]
KUR-CXCR4 Drug Info [543930]
NB-325 Drug Info [543930]
SURADISTA Drug Info [526483]
Binder KRH-2731 Drug Info [536143]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Cytokine-cytokine receptor interaction
Chemokine signaling pathway
Endocytosis
Axon guidance
Leukocyte transendothelial migration
Intestinal immune network for IgA production
Pathways in cancer
NetPath Pathway IL2 Signaling Pathway
IL4 Signaling Pathway
Leptin Signaling Pathway
PANTHER Pathway Axon guidance mediated by Slit/Robo
Inflammation mediated by chemokine and cytokine signaling pathway
Pathway Interaction Database S1P3 pathway
CXCR4-mediated signaling events
Syndecan-4-mediated signaling events
HIF-1-alpha transcription factor network
Ephrin B reverse signaling
Reactome Binding and entry of HIV virion
Chemokine receptors bind chemokines
G alpha (i) signalling events
WikiPathways GPCRs, Class A Rhodopsin-like
Hematopoietic Stem Cell Differentiation
HIV Life Cycle
Cardiac Progenitor Differentiation
Peptide GPCRs
GPCR ligand binding
GPCR downstream signaling
References
Ref 521607ClinicalTrials.gov (NCT00089466) Safety and Activity of the Oral HIV Entry Inhibitor AMD11070 in HIV Infected Patients. U.S. National Institutes of Health.
Ref 522865ClinicalTrials.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 523007ClinicalTrials.gov (NCT01105403) Exploratory Study on POL6326 in Stem Cell Mobilization. U.S. National Institutes of Health.
Ref 523067ClinicalTrials.gov (NCT01139788) A Study of LY2624587 in Patients With Advanced Cancer. U.S. National Institutes of Health.
Ref 523519ClinicalTrials.gov (NCT01374503) First in Man Study of ALX-0651, a Nanobody Inhibiting CXCR4. U.S. National Institutes of Health.
Ref 525014ClinicalTrials.gov (NCT02305563) Phase 1 Study of BMS-936564. U.S. National Institutes of Health.
Ref 525271ClinicalTrials.gov (NCT02502968) BL-8040 Addition to Consolidation Therapy in AML Patients.
Ref 5299412008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.
Ref 530179A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer. J Surg Res. 2009 Aug;155(2):231-6.
Ref 537114Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
Ref 543136(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 543204(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 545728Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004409)
Ref 546869Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010770)
Ref 547903Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020279)
Ref 548105Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021975)
Ref 548672Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027582)
Ref 523067ClinicalTrials.gov (NCT01139788) A Study of LY2624587 in Patients With Advanced Cancer. U.S. National Institutes of Health.
Ref 526483Suradista NSC 651016 inhibits the angiogenic activity of CXCL12-stromal cell-derived factor 1alpha. Clin Cancer Res. 2002 Dec;8(12):3955-60.
Ref 527153Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11791-6. Epub 2004 Jul 28.Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury.
Ref 528618J Med Chem. 2007 Jan 25;50(2):192-8.Structure-activity relationships of cyclic peptide-based chemokine receptor CXCR4 antagonists: disclosing the importance of side-chain and backbone functionalities.
Ref 529115J Med Chem. 2007 Nov 15;50(23):5655-64. Epub 2007 Oct 24.Discovery of small molecule CXCR4 antagonists.
Ref 529526Bioorg Med Chem Lett. 2008 Jul 15;18(14):4124-9. Epub 2008 May 29.Identification of novel non-peptide CXCR4 antagonists by ligand-based design approach.
Ref 529840Orally 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 530179A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer. J Surg Res. 2009 Aug;155(2):231-6.
Ref 531347Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation. Inflammation. 2012 Feb;35(1):130-7.
Ref 531821CXCR4 inhibitors: tumor vasculature and therapeutic challenges. Recent Pat Anticancer Drug Discov. 2012 Sep;7(3):251-64.
Ref 532141BMS-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 532779CXCR4 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 534456A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science. 1997 Sep 12;277(5332):1656-9.
Ref 534819A 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 535860Comparative 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. Epub 2003 Nov 3.
Ref 536143Progress in targeting HIV-1 entry. Drug Discov Today. 2005 Aug 15;10(16):1085-94.
Ref 536630Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers. Antimicrob Agents Chemother. 2008 May;52(5):1630-4. Epub 2008 Feb 19.
Ref 536663Pharmacokinetic 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 537114Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
Ref 543930(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 544156Therapeutic antibodies directed at G protein-coupled receptors. MAbs. 2010 Nov-Dec; 2(6): 594-606.
Ref 550382The CXCR4 Antagonist BL-8040 Efficiently Induces Apoptosis and Inhibits The Survival Of AML Cells. November 15, 2013; Blood: 122 (21).
Ref 551900CN patent application no. 101094684, With the combination of chemokine activation progenitor cells/stem cells.

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