Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTISGW7L)

• DOT Name: C-X-C chemokine receptor type 2 (CXCR2)
• Synonyms: CXC-R2; CXCR-2; CDw128b; GRO/MGSA receptor; High affinity interleukin-8 receptor B; IL-8R B; IL-8 receptor type 2; CD antigen CD182
• Gene Name: CXCR2
• Related Disease:
  WHIM syndrome 2
  Autosomal recessive severe congenital neutropenia due to CXCR2 deficiency
• UniProt ID: CXCR2_HUMAN
• PDB ID: 4Q3H; 5TYT; 6KVA; 6KVF; 6LFM; 6LFO
• Pfam ID: PF00001
• Sequence:
  MEDFNMESDSFEDFWKGEDLSNYSYSSTLPPFLLDAAPCEPESLEINKYFVVIIYALVFL
  LSLLGNSLVMLVILYSRVGRSVTDVYLLNLALADLLFALTLPIWAASKVNGWIFGTFLCK
  VVSLLKEVNFYSGILLLACISVDRYLAIVHATRTLTQKRYLVKFICLSIWGLSLLLALPV
  LLFRRTVYSSNVSPACYEDMGNNTANWRMLLRILPQSFGFIVPLLIMLFCYGFTLRTLFK
  AHMGQKHRAMRVIFAVVLIFLLCWLPYNLVLLADTLMRTQVIQETCERRNHIDRALDATE
  ILGILHSCLNPLIYAFIGQKFRHGLLKILAIHGLISKDSLPKDSRPSFVGSSSGHTSTTL
• Function: Receptor for interleukin-8 which is a powerful neutrophil chemotactic factor. Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. Binds to IL-8 with high affinity. Also binds with high affinity to CXCL3, GRO/MGSA and NAP-2.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Human cytomegalovirus infection (hsa05163)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Neutrophil degranulation (R-HSA-6798695)
  Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
WHIM syndrome 2	DISPPT30	Strong	Autosomal recessive	[1]
Autosomal recessive severe congenital neutropenia due to CXCR2 deficiency	DIS8TTXF	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of C-X-C chemokine receptor type 2 (CXCR2).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[8]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[9]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[10]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[11]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[12]
PBI-05204	DM05WIU	Phase 2	PBI-05204 increases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[13]
Lipoteichoic acid	DMEMRW0	Phase 1/2	Lipoteichoic acid decreases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of C-X-C chemokine receptor type 2 (CXCR2).	[15]

References

• [1] CXCR2 deficiency confers impaired neutrophil recruitment and increased susceptibility during Toxoplasma gondii infection. J Immunol. 2001 Dec 1;167(11):6503-9. doi: 10.4049/jimmunol.167.11.6503.
• [2] Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nat Genet. 2014 Jun;46(6):629-34. doi: 10.1038/ng.2962. Epub 2014 Apr 28.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Reciprocal regulation of 17beta-estradiol, interleukin-6 and interleukin-8 during growth and progression of epithelial ovarian cancer. Cytokine. 2009 Jun;46(3):382-91. doi: 10.1016/j.cyto.2009.03.013. Epub 2009 Apr 28.
• [6] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [9] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [10] Immunological consequences of thalidomide treatment in Sj?gren's syndrome. Ann Rheum Dis. 2006 Jan;65(1):112-4. doi: 10.1136/ard.2005.038406.
• [11] CXCR2 Expression on neutrophils is upregulated during the relapsing phase of ocular Behcet disease. Curr Eye Res. 2005 Mar;30(3):195-203. doi: 10.1080/02713680490904331.
• [12] Curcumin inhibits interleukin 8 production and enhances interleukin 8 receptor expression on the cell surface:impact on human pancreatic carcinoma cell growth by autocrine regulation. Cancer. 2002 Sep 15;95(6):1206-14. doi: 10.1002/cncr.10812.
• [13] Short-term exposure to oleandrin enhances responses to IL-8 by increasing cell surface IL-8 receptors. Br J Pharmacol. 2014 Jul;171(14):3339-51. doi: 10.1111/bph.12493.
• [14] Expression of the chemokine receptors CXCR1 and CXCR2 on granulocytes in human endotoxemia and tuberculosis: involvement of the p38 mitogen-activated protein kinase pathway. J Infect Dis. 2000 Sep;182(3):888-94. doi: 10.1086/315750. Epub 2000 Aug 17.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.