Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTBID49)

• DTT 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
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: CXCR4_HUMAN
• TTD ID: T96079
• Sequence:
  MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSIIFLTGIVGNGLVI
  LVMGYQKKLRSMTDKYRLHLSVADLLFVITLPFWAVDAVANWYFGNFLCKAVHVIYTVNL
  YSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKVVYVGVWIPALLLTIPDFIFANVSEA
  DDRYICDRFYPNDLWVVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKT
  TVILILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPI
  LYAFLGAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS
• 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.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Chemokine signaling pathway (hsa04062)
  Endocytosis (hsa04144)
  Axon guidance (hsa04360)
  Leukocyte transendothelial migration (hsa04670)
  Intestinal immune network for IgA production (hsa04672)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Chemokine receptors bind chemokines (R-HSA-380108)
  G alpha (i) signalling events (R-HSA-418594)
  Binding and entry of HIV virion (R-HSA-173107)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Motixafortide	DMW34B1	Multiple myeloma	2A83	Approved	[2]
Plerixafor	DMCJN1P	Non-hodgkin lymphoma	2B33.5	Approved	[1]

14 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AMD-070	DMVOY6B	Whim syndrome	4A00.Y	Phase 3	[3]
Balixafortide	DMUOFAC	Metastatic breast cancer	2C6Y	Phase 3	[4]
Ulocuplumab	DM6PMNR	Multiple myeloma	2A83	Phase 3	[5]
POL-6326	DM4OT29	Human immunodeficiency virus infection	1C62	Phase 2	[6]
TG-0054	DM2ZLWH	Macular degeneration	9B78.3	Phase 2	[7]
CTCE-9908	DM95XR8	Sarcoma	2A60-2C35	Phase 1/2	[8]
USL311	DM6HPEC	Recurring respiratory infection	CA07-CA45	Phase 1/2	[9]
ALX-0651	DMIRYM8	Haematological malignancy	2B33.Y	Phase 1	[10]
BMS-936564	DMS4H1J	Acute myeloid leukaemia	2A60	Phase 1	[11]
CTCE-0214	DM2HES0	Constitutional neutropenia	4B00.0	Phase 1	[12]
GMI-1359	DML1KSA	Breast cancer	2C60-2C65	Phase 1	[13]
LY2624587	DM289Z4	Metastatic cancer	2D50-2E2Z	Phase 1	[14]
MSX-122	DM1N9YS	Solid tumour/cancer	2A00-2F9Z	Phase 1	[15]
PF-06747143	DM2ZJ1C	Acute myeloid leukaemia	2A60	Phase 1	[5]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Garnocestim	DMCZAJW	Bone marrow transplantation	QB63.6	Discontinued in Phase 1	[16]
SURADISTA	DM1Z42H	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[17]
KRH-2731	DM2L0VF	Human immunodeficiency virus infection	1C62	Terminated	[19]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MAb173	DM5IMAU	Kaposi sarcoma	2B57	Preclinical	[18]

41 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AT-009	DMCO2S4	Solid tumour/cancer	2A00-2F9Z	Investigative	[20]
ATI-2341	DMLDWHP	Bone marrow transplantation	QB63.6	Investigative	[20]
CTCE-0324	DMEGZHF	Peripheral vascular disease	BD4Z	Investigative	[20]
CX-02	DMXMIT4	Solid tumour/cancer	2A00-2F9Z	Investigative	[20]
CXCL8	DMG1SXD	Psoriasis vulgaris	EA90	Investigative	[21]
CXCR4 gene disrupted T cells	DMNSUD9	Human immunodeficiency virus infection	1C62	Investigative	[20]
Cyclo(-D-Ala-D-Arg-L-Arg-L-Nal-Gly-)	DMLY8CU	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-MeTyr-D-Arg-L-Arg-L-Nal-Gly-)	DMBKRQ9	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-MeTyr-L-Arg-L-Arg-L-Nal-Gly-)	DMHI0UL	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-Arg-Arg-Nal-Gly-)	DM82C6Q	Discovery agent	N.A.	Investigative	[23]
Cyclo(-D-Tyr-D-Ala-L-Arg-L-Nal-Gly-)	DM8RKT1	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-MeNal-Gly-)	DM8XVAW	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-beta-Ala-)	DMWFITM	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-D-Ala-)	DMSA0IW	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-Gly-)	DMGOW1E	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-L-Ala-)	DM3PRHF	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-L-Pic-)	DMS9QHI	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-Sar-)	DM3Y1TZ	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-D-Arg-L-MeArg-L-Nal-Gly-)	DMUWC5O	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-D-MeArg-L-Arg-L-Nal-Gly-)	DM8F5DY	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-L-Ala-L-Arg-L-Nal-Gly-)	DMPW9SD	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-Ala-Sar-)	DMOWT4H	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-MeNal-Gly-)	DMPZ316	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-beta-Ala-)	DMNQWBS	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-D-Ala-)	DMV6C9N	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-Gly-)	DMH9VMO	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-L-Ala-)	DM72HW3	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-L-Arg-L-MeArg-L-Nal-Gly-)	DMSPKWD	Discovery agent	N.A.	Investigative	[22]
Cyclo(-D-Tyr-L-MeArg-L-Arg-L-Nal-Gly-)	DMIUVQ6	Discovery agent	N.A.	Investigative	[22]
GSK-812397	DMT98PA	Human immunodeficiency virus-1 infection	1C62	Investigative	[20]
isothiourea-1a	DMAYOTF	Discovery agent	N.A.	Investigative	[24]
isothiourea-1t	DMBX4WR	Discovery agent	N.A.	Investigative	[24]
KUR-CXCR4	DMPKDJ4	Discovery agent	N.A.	Investigative	[20]
LP-0067	DMWTJ3E	Autoimmune diabetes	5A10	Investigative	[20]
NB-325	DM7K36E	Human immunodeficiency virus infection	1C62	Investigative	[20]
ND-401	DMT0NQS	Human immunodeficiency virus infection	1C62	Investigative	[20]
T134	DM6HZVC	Discovery agent	N.A.	Investigative	[25]
T140	DMIHBC5	Discovery agent	N.A.	Investigative	[25]
T22	DMBIH8A	Discovery agent	N.A.	Investigative	[25]
TN-14003	DME0I7O	Acute lymphoblastic leukaemia	2A85	Investigative	[26]
viral macrophage inflammatory protein-II	DMAXOPS	Discovery agent	N.A.	Investigative	[27]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	7.10E-15	-0.4	-0.69
Sarcoma	2C82	Muscle tissue	3.40E-206	2.47	4.78
Multiple myeloma	2C82	Bone marrow	8.30E-02	-0.22	-0.36

References

• [1] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [2] The CXCR4 Antagonist BL-8040 Efficiently Induces Apoptosis and Inhibits The Survival Of AML Cells. November 15, 2013; Blood: 122 (21).
• [3] 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.
• [4] Anti-ageing pipeline starts to mature.Nat Rev Drug Discov. 2018 Sep;17(9):609-612.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] CXCR4 inhibitors: tumor vasculature and therapeutic challenges. Recent Pat Anticancer Drug Discov. 2012 Sep;7(3):251-64.
• [7] 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.
• [8] A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer. J Surg Res. 2009 Aug;155(2):231-6.
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Therapeutic antibodies directed at G protein-coupled receptors. MAbs. 2010 Nov-Dec; 2(6): 594-606.
• [11] 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.
• [12] Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation. Inflammation. 2012 Feb;35(1):130-7.
• [13] Clinical pipeline report, company report or official report of GlycoMimetics.
• [14] Inhibition of CXCR4 by LY2624587, a Fully Humanized Anti-CXCR4 Antibody Induces Apoptosis of Hematologic Malignancies. PLoS One. 2016 Mar 8;11(3):e0150585.
• [15] 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.
• [16] CN patent application no. 101094684, With the combination of chemokine activation progenitor cells/stem cells.
• [17] Suradista NSC 651016 inhibits the angiogenic activity of CXCL12-stromal cell-derived factor 1alpha. Clin Cancer Res. 2002 Dec;8(12):3955-60.
• [18] 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.
• [19] Progress in targeting HIV-1 entry. Drug Discov Today. 2005 Aug 15;10(16):1085-94.
• [20] 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).
• [21] 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.
• [22] 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.
• [23] Identification of novel non-peptide CXCR4 antagonists by ligand-based design approach. Bioorg Med Chem Lett. 2008 Jul 15;18(14):4124-9.
• [24] 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.
• [25] 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.
• [26] Discovery of small molecule CXCR4 antagonists. J Med Chem. 2007 Nov 15;50(23):5655-64.
• [27] A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science. 1997 Sep 12;277(5332):1656-9.