Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT68KZ9B)

• DOT Name: C-C chemokine receptor type 4 (CCR4)
• Synonyms: C-C CKR-4; CC-CKR-4; CCR-4; CCR4; K5-5; CD antigen CD194
• Gene Name: CCR4
• UniProt ID: CCR4_HUMAN
• Pfam ID: PF00001
• Sequence:
  MNPTDIADTTLDESIYSNYYLYESIPKPCTKEGIKAFGELFLPPLYSLVFVFGLLGNSVV
  VLVLFKYKRLRSMTDVYLLNLAISDLLFVFSLPFWGYYAADQWVFGLGLCKMISWMYLVG
  FYSGIFFVMLMSIDRYLAIVHAVFSLRARTLTYGVITSLATWSVAVFASLPGFLFSTCYT
  ERNHTYCKTKYSLNSTTWKVLSSLEINILGLVIPLGIMLFCYSMIIRTLQHCKNEKKNKA
  VKMIFAVVVLFLGFWTPYNIVLFLETLVELEVLQDCTFERYLDYAIQATETLAFVHCCLN
  PIIYFFLGEKFRKYILQLFKTCRGLFVLCQYCGLLQIYSADTPSSSYTQSTMDHDLHDAL
• Function: High affinity receptor for the C-C type chemokines CCL17/TARC, CCL22/MDC and CKLF isoform 1/CKLF1. The activity of this receptor is mediated by G(i) proteins which activate a phosphatidylinositol-calcium second messenger system. Can function as a chemoattractant homing receptor on circulating memory lymphocytes and as a coreceptor for some primary HIV-2 isolates. In the CNS, could mediate hippocampal-neuron survival.
• Tissue Specificity: Predominantly expressed in the thymus, in peripheral blood leukocytes, including T-cells, mostly CD4+ cells, and basophils, and in platelets; at lower levels, in the spleen and in monocytes . Detected also in macrophages, IL-2-activated natural killer cells and skin-homing memory T-cells, mostly the ones expressing the cutaneous lymphocyte antigen (CLA). Expressed in brain microvascular and coronary artery endothelial cells .
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clavulanate	DM2FGRT	Approved	C-C chemokine receptor type 4 (CCR4) increases the Liver injury ADR of Clavulanate.	[9]
Amoxicillin	DMUYNEI	Approved	C-C chemokine receptor type 4 (CCR4) increases the Liver injury ADR of Amoxicillin.	[9]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of C-C chemokine receptor type 4 (CCR4).	[1]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of C-C chemokine receptor type 4 (CCR4).	[2]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of C-C chemokine receptor type 4 (CCR4).	[3]
GSK618334	DMJPXZ4	Phase 1	GSK618334 decreases the expression of C-C chemokine receptor type 4 (CCR4).	[5]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of C-C chemokine receptor type 4 (CCR4).	[8]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of C-C chemokine receptor type 4 (CCR4).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of C-C chemokine receptor type 4 (CCR4).	[6]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane affects the methylation of C-C chemokine receptor type 4 (CCR4).	[7]

References

• [1] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [2] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [3] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [4] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [5] Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability. Muscle Nerve. 2017 Dec;56(6):1077-1084. doi: 10.1002/mus.25733. Epub 2017 Aug 29.
• [6] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [7] Effects of sulforaphane and 3,3'-diindolylmethane on genome-wide promoter methylation in normal prostate epithelial cells and prostate cancer cells. PLoS One. 2014 Jan 22;9(1):e86787. doi: 10.1371/journal.pone.0086787. eCollection 2014.
• [8] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [9] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.