Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: C-C chemokine receptor type 2 (CCR2)
• Synonyms: Monocyte chemoattractant protein 1 receptor; MCP-1-R; Chemokine receptor CCR2B; CMKBR2; CD192; CCR-2; CC-CKR-2; C-C CKR-2
• Gene Name: CCR2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: CCR2_HUMAN
• TTD ID: T89988
• Sequence:
  MLSTSRSRFIRNTNESGEEVTTFFDYDYGAPCHKFDVKQIGAQLLPPLYSLVFIFGFVGN
  MLVVLILINCKKLKCLTDIYLLNLAISDLLFLITLPLWAHSAANEWVFGNAMCKLFTGLY
  HIGYFGGIFFIILLTIDRYLAIVHAVFALKARTVTFGVVTSVITWLVAVFASVPGIIFTK
  CQKEDSVYVCGPYFPRGWNNFHTIMRNILGLVLPLLIMVICYSGILKTLLRCRNEKKRHR
  AVRVIFTIMIVYFLFWTPYNIVILLNTFQEFFGLSNCESTSQLDQATQVTETLGMTHCCI
  NPIIYAFVGEKFRSLFHIALGCRIAPLQKPVCGGPGVRPGKNVKVTTQGLLDGRGKGKSI
  GRAPEASLQDKEGA
• Function: Its binding with CCL2 on monocytes and macrophages mediates chemotaxis and migration induction through the activation of the PI3K cascade, the small G protein Rac and lamellipodium protrusion. Also acts as a receptor for the beta-defensin DEFB106A/DEFB106B. Regulates the expression of T-cell inflammatory cytokines and T-cell differentiation, promoting the differentiation of T-cells into T-helper 17 cells (Th17) during inflammation. Faciltates the export of mature thymocytes by enhancing directional movement of thymocytes to sphingosine-1-phosphate stimulation and up-regulation of S1P1R expression; signals through the JAK-STAT pathway to regulate FOXO1 activity leading to an increased expression of S1P1R. Plays an important role in mediating peripheral nerve injury-induced neuropathic pain. Increases NMDA-mediated synaptic transmission in both dopamine D1 and D2 receptor-containing neurons, which may be caused by MAPK/ERK-dependent phosphorylation of GRIN2B/NMDAR2B. Mediates the recruitment of macrophages and monocytes to the injury site following brain injury. Key functional receptor for CCL2 but can also bind CCL7 and CCL12.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Chemokine signaling pathway (hsa04062)
• Reactome Pathway:
  Chemokine receptors bind chemokines (R-HSA-380108)
  G alpha (i) signalling events (R-HSA-418594)
  Beta defensins (R-HSA-1461957)

Molecular Interaction Atlas (MIA) of This DTT

11 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD-2423	DMF34UY	Chronic obstructive pulmonary disease	CA22	Phase 2	[2]
BMS-813160	DMKY638	Diabetic nephropathy	GB61.Z	Phase 2	[3]
CCX-140	DMJ9XCO	Diabetic nephropathy	GB61.Z	Phase 2	[1]
CCX872	DMPVAUT	Pancreatic tumour	2C10	Phase 2	[4]
Cenicriviroc	DM4V8WF	Human immunodeficiency virus infection	1C62	Phase 2	[5]
MK-0812	DMRT8K4	Multiple sclerosis	8A40	Phase 2	[6]
MLN1202	DM24SOL	Metastatic cancer	2D50-2E2Z	Phase 2	[7]
Aminoguanidine	DMJQDUC	Diabetic retinopathy	9B71.0	Phase 1	[8]
CNTX-6970	DMCOJM7	Inflammatory pain	MG30.42	Phase 1	[9]
OPL-CCL2-LPM	DM3HOUX	Arthritis	FA20	Phase 1	[10]
TAK-202	DMVYEFZ	Melanoma	2C30	Phase 1	[11]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CCX915	DMHMST3	Multiple sclerosis	8A40	Discontinued in Phase 1	[12]
INCB8696	DM8PTUC	Multiple sclerosis	8A40	Discontinued in Phase 1	[13]
AZD-6942	DMZ90OV	Rheumatoid arthritis	FA20	Terminated	[15]
INCB3344	DMW39DV	Arteriosclerosis	BD40	Terminated	[16]
SB-282241	DMZLKCF	Inflammation	1A00-CA43.1	Terminated	[15]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MCP-1	DMYEFKH	Rheumatoid arthritis	FA20	Preclinical	[7]
RS-504393	DMB9IPR	Chronic obstructive pulmonary disease	CA22	Preclinical	[14]

13 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(R)-3-(1'-Adamantanecarbonyl)amino-caprolactam	DMRZDM0	Discovery agent	N.A.	Investigative	[17]
(S)-3-(1'-Adamantanecarbonyl)amino-caprolactam	DMS5IHX	Discovery agent	N.A.	Investigative	[17]
(S)-3-(2',2'-Dimethyl-propionyl)amino-caprolactam	DMANICH	Discovery agent	N.A.	Investigative	[17]
BMS-A	DMI796T	Inflammation	1A00-CA43.1	Investigative	[18]
GSK-1344386B	DMHBUG5	Arteriosclerosis	BD40	Investigative	[18]
INCB-10820	DMZCHSD	Inflammation	1A00-CA43.1	Investigative	[18]
NSC-651016	DMWY39L	Discovery agent	N.A.	Investigative	[19]
RAP-103	DM961JG	Neuropathic pain	8E43.0	Investigative	[18]
RAP-310	DMP2DMB	Alzheimer disease	8A20	Investigative	[18]
RS-102895	DMF71B3	Discovery agent	N.A.	Investigative	[20]
RS-136270	DMEHN2L	Discovery agent	N.A.	Investigative	[20]
Teijin-lead_cmp_5	DMSMLRB	Discovery agent	N.A.	Investigative	[21]
viral macrophage inflammatory protein-II	DMAXOPS	Discovery agent	N.A.	Investigative	[22]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	3.06E-02	0.29	0.89
Coronary artery disease	BA80-BA8Z	Peripheral blood	8.69E-01	-0.08	-0.18
Chronic obstructive pulmonary disease	CA23	Lung tissue	5.21E-01	-0.2	-0.34
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	1.33E-01	0.1	0.41
Alzheimer's disease	8A00.0	Entorhinal cortex	5.26E-01	4.75E-03	0.03

References

• [1] Present and future in the treatment of diabetic kidney disease. J Diabetes Res. 2015;2015:801348.
• [2] CA patent application no. 841416, Method of selecting therapeutic indications.
• [3] A dual CCR2/CCR5 chemokine antagonist, BMS-813160. Expert Opin Ther Pat. 2011 Dec;21(12):1919-24.
• [4] Therapeutic use of a clinical stage CCR2 inhibitor, CCX872, in obesity-associated steatohepatitis. The Lancet Volume 383, Supplement 1, 26 February 2014, Pages S78.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Assessment of chemokine receptor function on monocytes in whole blood: In vitro and ex vivo evaluations of a CCR2 antagonist. J Immunol Methods. 2010 Jan 31;352(1-2):101-10.
• [7] Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
• [8] Incyte Announces Second Quarter 2005 Financial Results; Reports Positive Phase IIb Results for Reverset in Treatment-Experienced HIV Patients. Incyte Corporation. 2005.
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis. Clin Exp Immunol. 2009 February; 155(2): 295-303.
• [11] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [12] Marketed and experimental medicines for the treatment of multiple sclerosis. The Association of the British Pharmaceutical Industry. 2009.
• [13] Incyte. Product Development Pipeline.
• [14] Beneficial or detrimental effects of carotenoids contained in food: cell culture models. Mini Rev Med Chem. 2007 Nov;7(11):1120-8.
• [15] Patent EP2727944 A1.
• [16] Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile. Bioorg Med Chem Lett. 2011 May 1;21(9):2626-30.
• [17] Highly potent, orally available anti-inflammatory broad-spectrum chemokine inhibitors. J Med Chem. 2009 Jun 11;52(11):3591-5.
• [18] 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: 59).
• [19] Inhibition of in vitro and in vivo HIV replication by a distamycin analogue that interferes with chemokine receptor function: a candidate for chemo... J Med Chem. 1998 Jun 18;41(13):2184-93.
• [20] Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within t... J Biol Chem. 2000 Aug 18;275(33):25562-71.
• [21] CCR2: characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach. J Med Chem. 2003 Sep 11;46(19):4070-86.
• [22] A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science. 1997 Sep 12;277(5332):1656-9.