Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5MF5DJ)

• DOT Name: Placenta growth factor (PGF)
• Synonyms: PlGF
• Gene Name: PGF
• UniProt ID: PLGF_HUMAN
• PDB ID: 1FZV; 1RV6
• Pfam ID: PF00341
• Sequence:
  MPVMRLFPCFLQLLAGLALPAVPPQQWALSAGNGSSEVEVVPFQEVWGRSYCRALERLVD
  VVSEYPSEVEHMFSPSCVSLLRCTGCCGDENLHCVPVETANVTMQLLKIRSGDRPSYVEL
  TFSQHVRCECRHSPGRQSPDMPGDFRADAPSFLPPRRSLPMLFRMEWGCALTGSQSAVWP
  SSPVPEEIPRMHPGRNGKKQQRKPLREKMKPERCGDAVPRR
• Function: Growth factor active in angiogenesis and endothelial cell growth, stimulating their proliferation and migration. It binds to the receptor FLT1/VEGFR-1. Isoform PlGF-2 binds NRP1/neuropilin-1 and NRP2/neuropilin-2 in a heparin-dependent manner. Also promotes cell tumor growth.
• Tissue Specificity: While the three isoforms are present in most placental tissues, PlGF-2 is specific to early (8 week) placenta and only PlGF-1 is found in the colon and mammary carcinomas.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  VEGF binds to VEGFR leading to receptor dimerization (R-HSA-195399)
  VEGF ligand-receptor interactions (R-HSA-194313)

Molecular Interaction Atlas (MIA) of This DOT

1 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 Placenta growth factor (PGF).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Placenta growth factor (PGF).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Placenta growth factor (PGF).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Placenta growth factor (PGF).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Placenta growth factor (PGF).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Placenta growth factor (PGF).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Placenta growth factor (PGF).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Placenta growth factor (PGF).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Placenta growth factor (PGF).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Placenta growth factor (PGF).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Placenta growth factor (PGF).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Placenta growth factor (PGF).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Placenta growth factor (PGF).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Placenta growth factor (PGF).	[15]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of Placenta growth factor (PGF).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Placenta growth factor (PGF).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Placenta growth factor (PGF).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Placenta growth factor (PGF).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Placenta growth factor (PGF).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Placenta growth factor (PGF).	[21]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Placenta growth factor (PGF).	[22]
Manganese	DMKT129	Investigative	Manganese increases the expression of Placenta growth factor (PGF).	[23]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Placenta growth factor (PGF).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine	DMM2NSK	Approved	Adenosine increases the secretion of Placenta growth factor (PGF).	[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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [9] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [10] Adenosine and Cordycepin Accelerate Tissue Remodeling Process through Adenosine Receptor Mediated Wnt/-Catenin Pathway Stimulation by Regulating GSK3b Activity. Int J Mol Sci. 2021 May 25;22(11):5571. doi: 10.3390/ijms22115571.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovasc Drugs Ther. 2013 Feb;27(1):37-48. doi: 10.1007/s10557-012-6427-8.
• [14] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [22] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [23] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [24] Exposure to perfluorobutane sulfonate and perfluorooctanesulfonic acid disrupts the production of angiogenesis factors and stress responses in human placental syncytiotrophoblast. Reprod Toxicol. 2020 Dec;98:269-277. doi: 10.1016/j.reprotox.2020.10.013. Epub 2020 Nov 2.