Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIGS220)

• DOT Name: C-X-C chemokine receptor type 3 (CXCR3)
• Synonyms: CXC-R3; CXCR-3; CKR-L2; G protein-coupled receptor 9; Interferon-inducible protein 10 receptor; IP-10 receptor; CD antigen CD183
• Gene Name: CXCR3
• UniProt ID: CXCR3_HUMAN
• PDB ID: 8HNK; 8HNL; 8HNM; 8HNN; 8K2W; 8K2X
• Pfam ID: PF00001
• Sequence:
  MVLEVSDHQVLNDAEVAALLENFSSSYDYGENESDSCCTSPPCPQDFSLNFDRAFLPALY
  SLLFLLGLLGNGAVAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFG
  SGLCKVAGALFNINFYAGALLLACISFDRYLNIVHATQLYRRGPPARVTLTCLAVWGLCL
  LFALPDFIFLSAHHDERLNATHCQYNFPQVGRTALRVLQLVAGFLLPLLVMAYCYAHILA
  VLLVSRGQRRLRAMRLVVVVVVAFALCWTPYHLVVLVDILMDLGALARNCGRESRVDVAK
  SVTSGLGYMHCCLNPLLYAFVGVKFRERMWMLLLRLGCPNQRGLQRQPSSSRRDSSWSET
  SEASYSGL
• Function: [Isoform 1]: Receptor for the C-X-C chemokine CXCL9, CXCL10 and CXCL11 and mediates the proliferation, survival and angiogenic activity of human mesangial cells (HMC) through a heterotrimeric G-protein signaling pathway. Binds to CCL21. Probably promotes cell chemotaxis response; [Isoform 2]: Receptor for the C-X-C chemokine CXCL4 and also mediates the inhibitory activities of CXCL9, CXCL10 and CXCL11 on the proliferation, survival and angiogenic activity of human microvascular endothelial cells (HMVEC) through a cAMP-mediated signaling pathway. Does not promote cell chemotaxis respons. Interaction with CXCL4 or CXCL10 leads to activation of the p38MAPK pathway and contributes to inhibition of angiogenesis. Overexpression in renal cancer cells down-regulates expression of the anti-apoptotic protein HMOX1 and promotes apoptosis; [Isoform 3]: Mediates the activity of CXCL11.
• Tissue Specificity: Isoform 1 and isoform 2 are mainly expressed in heart, kidney, liver and skeletal muscle. Isoform 1 is also expressed in placenta. Isoform 2 is expressed in endothelial cells. Expressed in T-cells (at protein level).
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
• 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-X-C chemokine receptor type 3 (CXCR3) increases the Liver injury ADR of Clavulanate.	[11]
Amoxicillin	DMUYNEI	Approved	C-X-C chemokine receptor type 3 (CXCR3) increases the Liver injury ADR of Amoxicillin.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of C-X-C chemokine receptor type 3 (CXCR3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of C-X-C chemokine receptor type 3 (CXCR3).	[6]

9 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-X-C chemokine receptor type 3 (CXCR3).	[2]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of C-X-C chemokine receptor type 3 (CXCR3).	[3]
MLN4924	DMP36KD	Phase 3	MLN4924 affects the expression of C-X-C chemokine receptor type 3 (CXCR3).	[4]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of C-X-C chemokine receptor type 3 (CXCR3).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of C-X-C chemokine receptor type 3 (CXCR3).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of C-X-C chemokine receptor type 3 (CXCR3).	[8]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of C-X-C chemokine receptor type 3 (CXCR3).	[5]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of C-X-C chemokine receptor type 3 (CXCR3).	[9]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of C-X-C chemokine receptor type 3 (CXCR3).	[10]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] 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.
• [3] Repetitive nicotine exposure leads to a more malignant and metastasis-prone phenotype of SCLC: a molecular insight into the importance of quitting smoking during treatment. Toxicol Sci. 2010 Aug;116(2):467-76. doi: 10.1093/toxsci/kfq138. Epub 2010 May 10.
• [4] The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-B activation and induces apoptosis in chronic lymphocytic leukemia B cells. Clin Cancer Res. 2014 Mar 15;20(6):1576-89. doi: 10.1158/1078-0432.CCR-13-0987.
• [5] 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.
• [6] 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.
• [7] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.
• [10] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.
• [11] 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.