Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT2CEJG)

• DTT Name: C-C chemokine receptor type 5 (CCR5)
• Synonyms: HIV-1 fusion coreceptor; HIV-1 fusion co-receptor; Chemokine receptor CCR5; CMKBR5; CHEMR13; CD195 antigen; CD195; CCR-5; CC-CKR-5; C-C CKR-5
• Gene Name: CCR5
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: CCR5_HUMAN
• TTD ID: T09960
• Sequence:
  MDYQVSSPIYDINYYTSEPCQKINVKQIAARLLPPLYSLVFIFGFVGNMLVILILINCKR
  LKSMTDIYLLNLAISDLFFLLTVPFWAHYAAAQWDFGNTMCQLLTGLYFIGFFSGIFFII
  LLTIDRYLAVVHAVFALKARTVTFGVVTSVITWVVAVFASLPGIIFTRSQKEGLHYTCSS
  HFPYSQYQFWKNFQTLKIVILGLVLPLLVMVICYSGILKTLLRCRNEKKRHRAVRLIFTI
  MIVYFLFWAPYNIVLLLNTFQEFFGLNNCSSSNRLDQAMQVTETLGMTHCCINPIIYAFV
  GEKFRNYLLVFFQKHIAKRFCKCCSIFQQEAPERASSVYTRSTGEQEISVGL
• Function: May play a role in the control of granulocytic lineage proliferation or differentiation. Receptor for a number of inflammatory CC-chemokines including CCL3/MIP-1-alpha, CCL4/MIP-1-beta and RANTES and subsequently transduces a signal by increasing the intracellular calcium ion level.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Chemokine signaling pathway (hsa04062)
  Endocytosis (hsa04144)
  Toxoplasmosis (hsa05145)
  Viral carcinogenesis (hsa05203)
• 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

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Maraviroc	DMTL94F	Human immunodeficiency virus infection	1C62	Approved	[1]

15 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
E-913	DMUHS5Q	Human immunodeficiency virus infection	1C62	Phase 3	[2]
PRO-140	DMD1FTP	Human immunodeficiency virus infection	1C62	Phase 3	[3]
Vicriviroc	DMMTW9K	Human immunodeficiency virus infection	1C62	Phase 3	[4]
PRO 140	DMCGK6X	Human immunodeficiency virus-1 infection	1C62	Phase 2/3	[5]
INCB9471	DMMWC6F	Infectious disease	1A00-CA43.1	Phase 2a	[2]
BMS-813160	DMKY638	Diabetic nephropathy	GB61.Z	Phase 2	[6]
Cenicriviroc	DM4V8WF	Human immunodeficiency virus infection	1C62	Phase 2	[7]
GSK-706769	DMPLKAH	Human immunodeficiency virus infection	1C62	Phase 2	[8]
PF-232798	DM8T6KQ	Human immunodeficiency virus infection	1C62	Phase 2	[9]
SB-728-T	DMRWE5D	Human immunodeficiency virus infection	1C62	Phase 2	[10]
Cal-1	DMUZIRY	Human immunodeficiency virus-1 infection	1C62	Phase 1/2	[11]
CCR5 mab	DMCFMHR	Human immunodeficiency virus infection	1C62	Phase 1	[12]
INCB15050	DMW7CLY	Human immunodeficiency virus infection	1C62	Phase 1	[13]
Tak-220	DMW10HM	Human immunodeficiency virus-1 infection	1C62	Phase 1	[14]
VCH-286	DMMKUOZ	Human immunodeficiency virus infection	1C62	Phase 1	[15]

6 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GW873140	DMG6TS2	Human immunodeficiency virus-1 infection	1C62	Discontinued in Phase 3	[16]
AZD8566	DMIYEZG	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 1	[17]
SCH-C	DM8J9SF	Human immunodeficiency virus infection	1C62	Discontinued in Phase 1	[14]
AZD5672	DMQUX28	Rheumatoid arthritis	FA20	Terminated	[17]
CCR5Qb	DMAZB1R	Human immunodeficiency virus infection	1C62	Terminated	[18]
TAK-779	DM0TELR	Transplant rejection	NE84	Terminated	[2]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2-(4-chlorobenzyloxy)-5-bromophenyl)methanamine	DMA15WU	Discovery agent	N.A.	Investigative	[19]
4-(2-(4-chlorobenzyloxy)-5-bromobenzyl)morpholine	DMN97TC	Discovery agent	N.A.	Investigative	[20]
ANIBAMINE	DMJX1G9	Discovery agent	N.A.	Investigative	[21]
CMPD-167	DM9IPH4	Human immunodeficiency virus-1 infection	1C62	Investigative	[22]
GT-1282	DMNMITH	Autoimmune diabetes	5A10	Investigative	[23]
N-(2-(4-chlorobenzyloxy)-5-bromobenzyl)ethanamine	DM97Q6T	Discovery agent	N.A.	Investigative	[19]
NIFEVIROC	DMIK40C	Discovery agent	N.A.	Investigative	[24]
SCH-210971	DM42A1F	Discovery agent	N.A.	Investigative	[25]
VARIECOLIN	DMVBO78	Discovery agent	N.A.	Investigative	[26]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Chronic obstructive pulmonary disease	CA23	Lung tissue	5.10E-01	0.03	0.05
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	5.43E-01	1.04E-02	0.02
Rheumatoid arthritis	FA20	Synovial tissue	9.30E-01	-0.08	-0.11

References

• [1] Rapamycin enhances aplaviroc anti-HIV activity: implications for the clinical development of novel CCR5 antagonists. Antiviral Res. 2009 Jul;83(1):86-9.
• [2] Species selectivity of small-molecular antagonists for the CCR5 chemokine receptor. Int Immunopharmacol. 2007 Dec 5;7(12):1528-34.
• [3] Agonist-induced internalization of CC chemokine receptor 5 as a mechanism to inhibit HIV replication. J Pharmacol Exp Ther. 2011 Jun;337(3):655-62.
• [4] HIV entry: new insights and implications for patient management. Curr Opin Infect Dis. 2009 Feb;22(1):35-42.
• [5] The return of PRO 140, a CCR5-directed mAb. Curr Opin HIV AIDS. 2018 Jul;13(4):346-353.
• [6] A dual CCR2/CCR5 chemokine antagonist, BMS-813160. Expert Opin Ther Pat. 2011 Dec;21(12):1919-24.
• [7] The dual CCR5 and CCR2 inhibitor cenicriviroc does not redistribute HIV into extracellular space: implications for plasma viral load and intracellular DNA decline. J Antimicrob Chemother. 2015 Mar;70(3):750-6.
• [8] Tapping into combination pills for HIV. Nat Rev Drug Discov. 2009 Jun;8(6):439-40.
• [9] An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: the discovery of N-{(1S)-1-(3-fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]propyl}acetamide (PF-232798). J Med Chem. 2011 Jan 13;54(1):67-77.
• [10] Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. N Engl J Med. 2014 March 6; 370(10): 901-910.
• [11] Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor. Mol Ther Methods Clin Dev. 2014 Feb 12;1:11.
• [12] CCR5 Monoclonal Antibodies for HIV-1 Therapy. Curr Opin HIV AIDS. 2009 March; 4(2): 104-111.
• [13] Incyte. Product Development Pipeline.
• [14] Progress in targeting HIV-1 entry. Drug Discov Today. 2005 Aug 15;10(16):1085-94.
• [15] The Continuing Evolution of HIV-1 Therapy: Identification and Development of Novel Antiretroviral Agents Targeting Viral and Cellular Targets. Mol Biol Int. 2012;2012:401965.
• [16] In vitro and clinical investigation of the relationship between CCR5 receptor occupancy and anti-HIV activity of Aplaviroc. J Clin Pharmacol. 2008 Oct;48(10):1179-88.
• [17] Clinical pipeline report, company report or official report of AstraZeneca (2009).
• [18] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021743)
• [19] CCR5 receptor antagonists: discovery and SAR of novel 4-hydroxypiperidine derivatives. Bioorg Med Chem Lett. 2007 Apr 1;17(7):1883-7.
• [20] CCR5 receptor antagonists: discovery and SAR study of guanylhydrazone derivatives. Bioorg Med Chem Lett. 2007 Jan 1;17(1):231-4.
• [21] Isolation and structure of antagonists of chemokine receptor (CCR5). J Nat Prod. 2004 Jun;67(6):1036-8.
• [22] 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: 3651).
• [23] Reduced cardiac side-effect potential by introduction of polar groups: discovery of NIBR-1282, an orally bioavailable CCR5 antagonist which is acti... Bioorg Med Chem Lett. 2008 Mar 15;18(6):2000-5.
• [24] Determination of nifeviroc, a novel CCR5 antagonist: application to a pharmacokinetic study. J Pharm Biomed Anal. 2011 Nov 1;56(3):637-40.
• [25] Chemokine receptor CCR-5 inhibitors produced by Chaetomium globosum. J Nat Prod. 2006 Jul;69(7):1025-8.
• [26] Inhibition of the human chemokine receptor CCR5 by variecolin and variecolol and isolation of four new variecolin analogues, emericolins A-D, from ... J Nat Prod. 2004 Oct;67(10):1681-4.