Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEMJU68)

• DOT Name: Platelet factor 4 (PF4)
• Synonyms: PF-4; C-X-C motif chemokine 4; Iroplact; Oncostatin-A
• Gene Name: PF4
• UniProt ID: PLF4_HUMAN
• PDB ID: 1DN3; 1F9Q; 1F9R; 1F9S; 1PFM; 1PFN; 1RHP; 4R9W; 4R9Y; 4RAU
• Pfam ID: PF00048
• Sequence:
  MSSAAGFCASRPGLLFLGLLLLPLVVAFASAEAEEDGDLQCLCVKTTSQVRPRHITSLEV
  IKAGPHCPTAQLIATLKNGRKICLDLQAPLYKKIIKKLLES
• Function: Released during platelet aggregation. Neutralizes the anticoagulant effect of heparin because it binds more strongly to heparin than to the chondroitin-4-sulfate chains of the carrier molecule. Chemotactic for neutrophils and monocytes. Inhibits endothelial cell proliferation, the short form is a more potent inhibitor than the longer form.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
• Reactome Pathway:
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Chemokine receptors bind chemokines (R-HSA-380108)
  G alpha (i) signalling events (R-HSA-418594)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Platelet factor 4 (PF4).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Platelet factor 4 (PF4).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Platelet factor 4 (PF4).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Platelet factor 4 (PF4).	[4]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Platelet factor 4 (PF4).	[5]
Sertraline	DM0FB1J	Approved	Sertraline decreases the expression of Platelet factor 4 (PF4).	[6]
Fructose	DM43AN2	Approved	Fructose increases the expression of Platelet factor 4 (PF4).	[8]
Paroxetine	DM5PVQE	Approved	Paroxetine decreases the expression of Platelet factor 4 (PF4).	[9]
Nortriptyline	DM4KDYJ	Approved	Nortriptyline affects the expression of Platelet factor 4 (PF4).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Platelet factor 4 (PF4).	[10]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil decreases the expression of Platelet factor 4 (PF4).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Platelet factor 4 (PF4).	[13]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Platelet factor 4 (PF4).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ardeparin	DMYRX8B	Approved	Ardeparin increases the secretion of Platelet factor 4 (PF4).	[7]
adenosine diphosphate	DMFUHKP	Investigative	adenosine diphosphate increases the secretion of Platelet factor 4 (PF4).	[14]

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 affects the methylation of Platelet factor 4 (PF4).	[12]

References

• [1] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [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] 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.
• [4] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [5] Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans. Heart. 2000 Jun;83(6):688-95. doi: 10.1136/heart.83.6.688.
• [6] Relationship between release of platelet/endothelial biomarkers and plasma levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression. Am J Psychiatry. 2005 Jun;162(6):1165-70. doi: 10.1176/appi.ajp.162.6.1165.
• [7] Carotid endarterectomy in patients with heparin-induced platelet activation: comparative efficacy of aspirin and iloprost (ZK36374). J Vasc Surg. 1987 May;5(5):693-701.
• [8] Non-nutritional sweeteners effects on endothelial vascular function. Toxicol In Vitro. 2020 Feb;62:104694. doi: 10.1016/j.tiv.2019.104694. Epub 2019 Oct 23.
• [9] Evaluation of platelet activation in depressed patients with ischemic heart disease after paroxetine or nortriptyline treatment. J Clin Psychopharmacol. 2000 Apr;20(2):137-40. doi: 10.1097/00004714-200004000-00004.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] [Unstable stenocardia: indicators of platelet activity and the effect of verapamil]. Biull Vsesoiuznogo Kardiol Nauchn Tsentra AMN SSSR. 1987;10(2):33-9.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] The role of nanoparticle size in hemocompatibility. Toxicology. 2009 Apr 28;258(2-3):139-47. doi: 10.1016/j.tox.2009.01.015. Epub 2009 Jan 22.