Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5512B2)

• DOT Name: C-X-C chemokine receptor type 1 (CXCR1)
• Synonyms: CXC-R1; CXCR-1; CDw128a; High affinity interleukin-8 receptor A; IL-8R A; IL-8 receptor type 1; CD antigen CD181
• Gene Name: CXCR1
• UniProt ID: CXCR1_HUMAN
• PDB ID: 1ILP; 1ILQ; 2LNL; 6XMN; 8IC0
• Pfam ID: PF00001
• Sequence:
  MSNITDPQMWDFDDLNFTGMPPADEDYSPCMLETETLNKYVVIIAYALVFLLSLLGNSLV
  MLVILYSRVGRSVTDVYLLNLALADLLFALTLPIWAASKVNGWIFGTFLCKVVSLLKEVN
  FYSGILLLACISVDRYLAIVHATRTLTQKRHLVKFVCLGCWGLSMNLSLPFFLFRQAYHP
  NNSSPVCYEVLGNDTAKWRMVLRILPHTFGFIVPLFVMLFCYGFTLRTLFKAHMGQKHRA
  MRVIFAVVLIFLLCWLPYNLVLLADTLMRTQVIQESCERRNNIGRALDATEILGFLHSCL
  NPIIYAFIGQNFRHGFLKILAMHGLVSKEFLARHRVTSYTSSSVNVSSNL
• Function: Receptor to interleukin-8, which is a powerful neutrophils 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.
• 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)
• 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

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	C-X-C chemokine receptor type 1 (CXCR1) affects the response to substance of Arsenic.	[14]

15 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 1 (CXCR1).	[1]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[2]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[3]
Teriflunomide	DMQ2FKJ	Approved	Teriflunomide decreases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[4]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[6]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[7]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[8]
PBI-05204	DM05WIU	Phase 2	PBI-05204 increases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[11]
Sphingosine-1-Phosphate	DMJCQKA	Phase 1	Sphingosine-1-Phosphate decreases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[12]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[7]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[13]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[13]
LPA	DMI5XR1	Investigative	LPA decreases the expression of C-X-C chemokine receptor type 1 (CXCR1).	[12]

1 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 decreases the methylation of C-X-C chemokine receptor type 1 (CXCR1).	[10]

References

• [1] All-trans retinoic acid inhibits vascular endothelial growth factor expression in a cell model of neutrophil activation. Endocrinology. 2006 Mar;147(3):1264-70. doi: 10.1210/en.2005-0854. Epub 2005 Dec 1.
• [2] Effects of combined 17beta-estradiol with TCDD on secretion of chemokine IL-8 and expression of its receptor CXCR1 in endometriotic focus-associated cells in co-culture. Hum Reprod. 2006 Apr;21(4):870-9. doi: 10.1093/humrep/dei414. Epub 2006 Mar 3.
• [3] 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.
• [4] Differential modulation of pro- and anti-inflammatory cytokine receptors by N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxy-crotonic acid amide (A77 1726), the physiologically active metabolite of the novel immunomodulator leflunomide. Biochem Pharmacol. 1998 May 1;55(9):1523-9. doi: 10.1016/s0006-2952(97)00677-1.
• [5] 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.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Preliminary discovery of novel markers for human cell line activation test (h-CLAT). Toxicol In Vitro. 2021 Aug;74:105154. doi: 10.1016/j.tiv.2021.105154. Epub 2021 Mar 25.
• [8] Expression of neutrophil SOD2 is reduced after lipopolysaccharide stimulation: a potential cause of neutrophil dysfunction in chronic kidney disease. Nephrol Dial Transplant. 2011 Jul;26(7):2195-201. doi: 10.1093/ndt/gfq673. Epub 2010 Nov 2.
• [9] 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.
• [10] 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.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [12] Neutrophil sphingosine 1-phosphate and lysophosphatidic acid receptors in pneumonia. Am J Respir Cell Mol Biol. 2006 Feb;34(2):233-41. doi: 10.1165/rcmb.2005-0126OC. Epub 2005 Oct 13.
• [13] The THP-1 cell toolbox: a new concept integrating the key events of skin sensitization. Arch Toxicol. 2019 Apr;93(4):941-951.
• [14] Arsenic exposure, diabetes-related genes and diabetes prevalence in a general population from Spain. Environ Pollut. 2018 Apr;235:948-955. doi: 10.1016/j.envpol.2018.01.008. Epub 2018 Feb 21.