Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7DOXEM)

• DOT Name: C-C motif chemokine 21 (CCL21)
• Synonyms: 6Ckine; Beta-chemokine exodus-2; Secondary lymphoid-tissue chemokine; SLC; Small-inducible cytokine A21
• Gene Name: CCL21
• UniProt ID: CCL21_HUMAN
• PDB ID: 2L4N; 5EKI
• Pfam ID: PF00048
• Sequence:
  MAQSLALSLLILVLAFGIPRTQGSDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIP
  AILFLPRKRSQAELCADPKELWVQQLMQHLDKTPSPQKPAQGCRKDRGASKTGKKGKGSK
  GCKRTERSQTPKGP
• Function: Inhibits hemopoiesis and stimulates chemotaxis. Chemotactic in vitro for thymocytes and activated T-cells, but not for B-cells, macrophages, or neutrophils. Shows preferential activity towards naive T-cells. May play a role in mediating homing of lymphocytes to secondary lymphoid organs. Binds to atypical chemokine receptor ACKR4 and mediates the recruitment of beta-arrestin (ARRB1/2) to ACKR4.
• Tissue Specificity: Highly expressed in high endothelial venules of lymph nodes, spleen and appendix. Intermediate levels found in small intestine, thyroid gland and trachea. Low level expression in thymus, bone marrow, liver, and pancreas. Also found in tonsil, fetal heart and fetal spleen.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
  NF-kappa B sig.ling pathway (hsa04064)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of C-C motif chemokine 21 (CCL21).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of C-C motif chemokine 21 (CCL21).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of C-C motif chemokine 21 (CCL21).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of C-C motif chemokine 21 (CCL21).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of C-C motif chemokine 21 (CCL21).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of C-C motif chemokine 21 (CCL21).	[6]
Capecitabine	DMTS85L	Approved	Capecitabine decreases the expression of C-C motif chemokine 21 (CCL21).	[7]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone decreases the expression of C-C motif chemokine 21 (CCL21).	[8]
USNIC ACID	DMGOURX	Investigative	USNIC ACID increases the expression of C-C motif chemokine 21 (CCL21).	[10]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the secretion of C-C motif chemokine 21 (CCL21).	[5]

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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [3] Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells. Fertil Steril. 2009 Aug;92(2):709-21.
• [4] Pattern of expression of apoptosis and inflammatory genes in humans exposed to arsenic and/or fluoride. Sci Total Environ. 2010 Jan 15;408(4):760-7. doi: 10.1016/j.scitotenv.2009.11.016. Epub 2009 Dec 4.
• [5] Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard. Arch Toxicol. 2021 Feb;95(2):727-747. doi: 10.1007/s00204-020-02946-5. Epub 2021 Jan 25.
• [6] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [7] Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
• [8] The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594. doi: 10.1016/j.redox.2020.101594. Epub 2020 May 29.
• [9] 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.
• [10] Effects of usnic acid exposure on human hepatoblastoma HepG2 cells in culture. J Appl Toxicol. 2012 Sep;32(9):722-30.