Details of Drug Off-Target (DOT)

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

• DOT Name: High mobility group protein HMG-I/HMG-Y (HMGA1)
• Synonyms: HMG-I(Y); High mobility group AT-hook protein 1; High mobility group protein A1; High mobility group protein R
• Gene Name: HMGA1
• Related Disease: Non-insulin dependent diabetes
• UniProt ID: HMGA1_HUMAN
• PDB ID: 2EZD; 2EZE; 2EZF; 2EZG
• Sequence:
  MSESSSKSSQPLASKQEKDGTEKRGRGRPRKQPPVSPGTALVGSQKEPSEVPTPKRPRGR
  PKGSKNKGAAKTRKTTTTPGRKPRGRPKKLEKEEEEGISQESSEEEQ
• Function: HMG-I/Y bind preferentially to the minor groove of A+T rich regions in double-stranded DNA. It is suggested that these proteins could function in nucleosome phasing and in the 3'-end processing of mRNA transcripts. They are also involved in the transcription regulation of genes containing, or in close proximity to A+T-rich regions.
• Reactome Pathway:
  2-LTR circle formation (R-HSA-164843)
  Integration of viral DNA into host genomic DNA (R-HSA-175567)
  Autointegration results in viral DNA circles (R-HSA-177539)
  APOBEC3G mediated resistance to HIV-1 infection (R-HSA-180689)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  Formation of Senescence-Associated Heterochromatin Foci (SAHF) (R-HSA-2559584)
  Integration of provirus (R-HSA-162592)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	High mobility group protein HMG-I/HMG-Y (HMGA1) affects the response to substance of Mitomycin.	[26]
Topotecan	DMP6G8T	Approved	High mobility group protein HMG-I/HMG-Y (HMGA1) affects the response to substance of Topotecan.	[26]

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 High mobility group protein HMG-I/HMG-Y (HMGA1).	[2]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of High mobility group protein HMG-I/HMG-Y (HMGA1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[13]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[14]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[15]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[16]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[17]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[18]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[19]
Flavopiridol	DMKSUOI	Phase 2	Flavopiridol decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[24]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of High mobility group protein HMG-I/HMG-Y (HMGA1).	[12]

References

• [1] Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Nat Med. 2005 Jul;11(7):765-73. doi: 10.1038/nm1254. Epub 2005 May 29.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [12] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [13] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [14] NFATc4 mediates ethanol-triggered hepatocyte senescence. Toxicol Lett. 2021 Oct 10;350:10-21. doi: 10.1016/j.toxlet.2021.06.018. Epub 2021 Jun 27.
• [15] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [16] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [17] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [18] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [19] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [20] Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood. 2011 Mar 24;117(12):3302-10. doi: 10.1182/blood-2010-09-310862. Epub 2011 Jan 14.
• [21] 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.
• [22] 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.
• [23] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [26] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.