Target Information
| Target General Information | Top | |||||
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| Target ID |
T96079
(Former ID: TTDC00121)
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| Target Name |
C-X-C chemokine receptor type 4 (CXCR4)
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| 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
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| Gene Name |
CXCR4
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| Target Type |
Successful target
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[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.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSIIFLTGIVGNGLVI
LVMGYQKKLRSMTDKYRLHLSVADLLFVITLPFWAVDAVANWYFGNFLCKAVHVIYTVNL YSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKVVYVGVWIPALLLTIPDFIFANVSEA DDRYICDRFYPNDLWVVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKT TVILILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPI LYAFLGAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T64X48 | |||||
| Drugs and Modes of Action | Top | |||||
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| 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 | AMD-070 | Drug Info | Phase 3 | Whim syndrome | [4] | |
| 2 | Balixafortide | Drug Info | Phase 3 | Metastatic breast cancer | [5] | |
| 3 | BL-8040 | Drug Info | Phase 3 | Multiple myeloma | [6] | |
| 4 | Ulocuplumab | Drug Info | Phase 3 | Multiple myeloma | [7] | |
| 5 | POL-6326 | Drug Info | Phase 2 | Human immunodeficiency virus infection | [8] | |
| 6 | TG-0054 | Drug Info | Phase 2 | Macular degeneration | [9] | |
| 7 | CTCE-9908 | Drug Info | Phase 1/2 | Sarcoma | [10] | |
| 8 | USL311 | Drug Info | Phase 1/2 | Recurring respiratory infection | [11] | |
| 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 | [11] | |
| 13 | LY2624587 | 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 | [21] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | MAb173 | Drug Info | Preclinical | Kaposi sarcoma | [20] | |
| Mode of Action | [+] 5 Modes of Action | + | ||||
| Antagonist | [+] 21 Antagonist drugs | + | ||||
| 1 | Plerixafor | Drug Info | [1] | |||
| 2 | AMD-070 | Drug Info | [22], [23] | |||
| 3 | Balixafortide | Drug Info | [24] | |||
| 4 | BL-8040 | Drug Info | [25] | |||
| 5 | Ulocuplumab | Drug Info | [17], [26] | |||
| 6 | POL-6326 | Drug Info | [27] | |||
| 7 | USL311 | Drug Info | [11] | |||
| 8 | GMI-1359 | Drug Info | [32] | |||
| 9 | LY2624587 | Drug Info | [33] | |||
| 10 | MSX-122 | Drug Info | [34] | |||
| 11 | PF-06747143 | Drug Info | [17] | |||
| 12 | MAb173 | Drug Info | [37] | |||
| 13 | AT-009 | Drug Info | [39] | |||
| 14 | GSK-812397 | Drug Info | [39] | |||
| 15 | isothiourea-1a | Drug Info | [43] | |||
| 16 | isothiourea-1t | Drug Info | [43] | |||
| 17 | LP-0067 | Drug Info | [39] | |||
| 18 | T134 | Drug Info | [44] | |||
| 19 | T140 | Drug Info | [44] | |||
| 20 | T22 | Drug Info | [44] | |||
| 21 | viral macrophage inflammatory protein-II | Drug Info | [46] | |||
| Inhibitor | [+] 27 Inhibitor drugs | + | ||||
| 1 | TG-0054 | Drug Info | [28] | |||
| 2 | ALX-0651 | Drug Info | [29] | |||
| 3 | Cyclo(-D-Ala-D-Arg-L-Arg-L-Nal-Gly-) | Drug Info | [41] | |||
| 4 | Cyclo(-D-MeTyr-D-Arg-L-Arg-L-Nal-Gly-) | Drug Info | [41] | |||
| 5 | Cyclo(-D-MeTyr-L-Arg-L-Arg-L-Nal-Gly-) | Drug Info | [41] | |||
| 6 | Cyclo(-D-Tyr-Arg-Arg-Nal-Gly-) | Drug Info | [42] | |||
| 7 | Cyclo(-D-Tyr-D-Ala-L-Arg-L-Nal-Gly-) | Drug Info | [41] | |||
| 8 | Cyclo(-D-Tyr-D-Arg-L-Arg-L-MeNal-Gly-) | Drug Info | [41] | |||
| 9 | Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-beta-Ala-) | Drug Info | [41] | |||
| 10 | Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-D-Ala-) | Drug Info | [41] | |||
| 11 | Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-Gly-) | Drug Info | [41] | |||
| 12 | Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-L-Ala-) | Drug Info | [41] | |||
| 13 | Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-L-Pic-) | Drug Info | [41] | |||
| 14 | Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-Sar-) | Drug Info | [41] | |||
| 15 | Cyclo(-D-Tyr-D-Arg-L-MeArg-L-Nal-Gly-) | Drug Info | [41] | |||
| 16 | Cyclo(-D-Tyr-D-MeArg-L-Arg-L-Nal-Gly-) | Drug Info | [41] | |||
| 17 | Cyclo(-D-Tyr-L-Ala-L-Arg-L-Nal-Gly-) | Drug Info | [41] | |||
| 18 | Cyclo(-D-Tyr-L-Arg-L-Arg-L-Ala-Sar-) | Drug Info | [41] | |||
| 19 | Cyclo(-D-Tyr-L-Arg-L-Arg-L-MeNal-Gly-) | Drug Info | [41] | |||
| 20 | Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-beta-Ala-) | Drug Info | [41] | |||
| 21 | Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-D-Ala-) | Drug Info | [41] | |||
| 22 | Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-Gly-) | Drug Info | [41] | |||
| 23 | Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-L-Ala-) | Drug Info | [41] | |||
| 24 | Cyclo(-D-Tyr-L-Arg-L-MeArg-L-Nal-Gly-) | Drug Info | [41] | |||
| 25 | Cyclo(-D-Tyr-L-MeArg-L-Arg-L-Nal-Gly-) | Drug Info | [41] | |||
| 26 | ND-401 | Drug Info | [39] | |||
| 27 | TN-14003 | Drug Info | [45] | |||
| Modulator | [+] 8 Modulator drugs | + | ||||
| 1 | CTCE-9908 | Drug Info | [10] | |||
| 2 | BMS-936564 | Drug Info | [30] | |||
| 3 | Garnocestim | Drug Info | [35] | |||
| 4 | SURADISTA | Drug Info | [36] | |||
| 5 | CTCE-0324 | Drug Info | [39] | |||
| 6 | CXCR4 gene disrupted T cells | Drug Info | [39] | |||
| 7 | KUR-CXCR4 | Drug Info | [39] | |||
| 8 | NB-325 | Drug Info | [39] | |||
| Agonist | [+] 3 Agonist drugs | + | ||||
| 1 | CTCE-0214 | Drug Info | [31] | |||
| 2 | ATI-2341 | Drug Info | [39] | |||
| 3 | CXCL8 | Drug Info | [40] | |||
| Binder | [+] 1 Binder drugs | + | ||||
| 1 | KRH-2731 | 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 | |||||
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| Co-Targets | ||||||
| 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-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| 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 | ClinicalTrials.gov (NCT03995108) Efficacy and Safety Study of Mavorixafor in Participants With Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) Syndrome. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT03786094) Pivotal Study in HER2 Negative, Locally Recurrent or Metastatic Breast Cancer (FORTRESS). U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT03246529) A Phase III, Safety, Tolerability and Efficacy of Combination Treatment of BL-8040 and G-GSF as Compared to Placebo and G-CSF for thE MobilizatioN of HematopoiEtic Stem Cells for Autologous TransplantatIon in SubjectS With MM (GENESIS). U.S. National Institutes of Health. | |||||
| REF 7 | Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat Rev Drug Discov. 2017 Sep 1;16(9):661. | |||||
| REF 8 | ClinicalTrials.gov (NCT01105403) Exploratory Study on POL6326 in Stem Cell Mobilization. U.S. National Institutes of Health. | |||||
| REF 9 | 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 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 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| 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 | AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer. 2019 Nov 4;18(1):153. | |||||
| REF 21 | 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 22 | 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 23 | 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 24 | Anti-ageing pipeline starts to mature.Nat Rev Drug Discov. 2018 Sep;17(9):609-612. | |||||
| REF 25 | The CXCR4 Antagonist BL-8040 Efficiently Induces Apoptosis and Inhibits The Survival Of AML Cells. November 15, 2013; Blood: 122 (21). | |||||
| REF 26 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 27 | CXCR4 inhibitors: tumor vasculature and therapeutic challenges. Recent Pat Anticancer Drug Discov. 2012 Sep;7(3):251-64. | |||||
| REF 28 | 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 29 | Therapeutic antibodies directed at G protein-coupled receptors. MAbs. 2010 Nov-Dec; 2(6): 594-606. | |||||
| REF 30 | 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 31 | Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation. Inflammation. 2012 Feb;35(1):130-7. | |||||
| REF 32 | Clinical pipeline report, company report or official report of GlycoMimetics. | |||||
| REF 33 | Inhibition of CXCR4 by LY2624587, a Fully Humanized Anti-CXCR4 Antibody Induces Apoptosis of Hematologic Malignancies. PLoS One. 2016 Mar 8;11(3):e0150585. | |||||
| REF 34 | 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 35 | CN patent application no. 101094684, With the combination of chemokine activation progenitor cells/stem cells. | |||||
| REF 36 | Suradista NSC 651016 inhibits the angiogenic activity of CXCL12-stromal cell-derived factor 1alpha. Clin Cancer Res. 2002 Dec;8(12):3955-60. | |||||
| REF 37 | Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120). Virology. 2000 Mar 15;268(2):329-44. | |||||
| REF 38 | Progress in targeting HIV-1 entry. Drug Discov Today. 2005 Aug 15;10(16):1085-94. | |||||
| REF 39 | 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 40 | 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 41 | 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 42 | Identification of novel non-peptide CXCR4 antagonists by ligand-based design approach. Bioorg Med Chem Lett. 2008 Jul 15;18(14):4124-9. | |||||
| REF 43 | 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 44 | 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 45 | Discovery of small molecule CXCR4 antagonists. J Med Chem. 2007 Nov 15;50(23):5655-64. | |||||
| REF 46 | A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science. 1997 Sep 12;277(5332):1656-9. | |||||
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