Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3CUXA7)

• DOT Name: Protein HEG homolog 1 (HEG1)
• Gene Name: HEG1
• Related Disease:
  Cerebral cavernous malformation
  Schizophrenia
  Hepatocellular carcinoma
• UniProt ID: HEG1_HUMAN
• PDB ID: 3U7D; 4HDQ
• Pfam ID: PF00008 ; PF07645
• Sequence:
  MASPRASRWPPPLLLLLLPLLLLPPAAPGTRDPPPSPARRALSLAPLAGAGLELQLERRP
  EREPPPTPPRERRGPATPGPSYRAPEPGAATQRGPSGRAPRGGSADAAWKHWPESNTEAH
  VENITFYQNQEDFSTVSSKEGVMVQTSGKSHAASDAPENLTLLAETADARGRSGSSSRTN
  FTILPVGYSLEIATALTSQSGNLASESLHLPSSSSEFDERIAAFQTKSGTASEMGTERAM
  GLSEEWTVHSQEATTSAWSPSFLPALEMGELTTPSRKRNSSGPDLSWLHFYRTAASSPLL
  DLSSSSESTEKLNNSTGLQSSSVSQTKTMHVATVFTDGGPRTLRSLTVSLGPVSKTEGFP
  KDSRIATTSSSVLLSPSAVESRRNSRVTGNPGDEEFIEPSTENEFGLTSLRWQNDSPTFG
  EHQLASSSEVQNGSPMSQTETVSRSVAPMRGGEITAHWLLTNSTTSADVTGSSASYPEGV
  NASVLTQFSDSTVQSGGSHTALGDRSYSESSSTSSSESLNSSAPRGERSIAGISYGQVRG
  TAIEQRTSSDHTDHTYLSSTFTKGERALLSITDNSSSSDIVESSTSYIKISNSSHSEYSS
  FFHAQTERSNISSYDGEYAQPSTESPVLHTSNLPSYTPTINMPNTSVVLDTDAEFVSDSS
  SSSSSSSSSSSSGPPLPLPSVSQSHHLFSSILPSTRASVHLLKSTSDASTPWSSSPSPLP
  VSLTTSTSAPLSVSQTTLPQSSSTPVLPRARETPVTSFQTSTMTSFMTMLHSSQTADLKS
  QSTPHQEKVITESKSPSLVSLPTESTKAVTTNSPLPPSLTESSTEQTLPATSTNLAQMSP
  TFTTTILKTSQPLMTTPGTLSSTASLVTGPIAVQTTAGKQLSLTHPEILVPQISTEGGIS
  TERNRVIVDATTGLIPLTSVPTSAKEMTTKLGVTAEYSPASRSLGTSPSPQTTVVSTAED
  LAPKSATFAVQSSTQSPTTVSSSASVNSCAVNPCLHNGECVADNTSRGYHCRCPPSWQGD
  DCSVDVNECLSNPCPSTAMCNNTQGSFICKCPVGYQLEKGICNLVRTFVTEFKLKRTFLN
  TTVEKHSDLQEVENEITKTLNMCFSALPSYIRSTVHASRESNAVVISLQTTFSLASNVTL
  FDLADRMQKCVNSCKSSAEVCQLLGSQRRIFRAGSLCKRKSPECDKDTSICTDLDGVALC
  QCKSGYFQFNKMDHSCRACEDGYRLENETCMSCPFGLGGLNCGNPYQLITVVIAAAGGGL
  LLILGIALIVTCCRKNKNDISKLIFKSGDFQMSPYAEYPKNPRSQEWGREAIEMHENGST
  KNLLQMTDVYYSPTSVRNPELERNGLYPAYTGLPGSRHSCIFPGQYNPSFISDESRRRDY
  F
• Function: Receptor component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions.
• KEGG Pathway: Adherens junction (hsa04520)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebral cavernous malformation	DISLKNYA	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[3]

16 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 Protein HEG homolog 1 (HEG1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein HEG homolog 1 (HEG1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein HEG homolog 1 (HEG1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein HEG homolog 1 (HEG1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein HEG homolog 1 (HEG1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein HEG homolog 1 (HEG1).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein HEG homolog 1 (HEG1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein HEG homolog 1 (HEG1).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein HEG homolog 1 (HEG1).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Protein HEG homolog 1 (HEG1).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Protein HEG homolog 1 (HEG1).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein HEG homolog 1 (HEG1).	[14]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Protein HEG homolog 1 (HEG1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein HEG homolog 1 (HEG1).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein HEG homolog 1 (HEG1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein HEG homolog 1 (HEG1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein HEG homolog 1 (HEG1).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein HEG homolog 1 (HEG1).	[15]

References

• [1] Cerebral cavernous malformations arise independent of the heart of glass receptor.Stroke. 2014 May;45(5):1505-1509. doi: 10.1161/STROKEAHA.114.004809. Epub 2014 Mar 18.
• [2] Hemoencephalography self-regulation training and its impact on cognition: A study with schizophrenia and healthy participants.Schizophr Res. 2018 May;195:591-593. doi: 10.1016/j.schres.2017.08.044. Epub 2017 Sep 5.
• [3] A novel function for HEG1 in promoting metastasis in hepatocellular carcinoma.Clin Sci (Lond). 2019 Oct 15;133(19):2019-2022. doi: 10.1042/CS20190704.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.