Details of Drug Off-Target (DOT)

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

• DOT Name: High mobility group protein HMGI-C (HMGA2)
• Synonyms: High mobility group AT-hook protein 2
• Gene Name: HMGA2
• Related Disease:
  Silver-Russell syndrome 5
  Uterine fibroids
• UniProt ID: HMGA2_HUMAN
• Pfam ID: PF02178
• Sequence:
  MSARGEGAGQPSTSAQGQPAAPAPQKRGRGRPRKQQQEPTGEPSPKRPRGRPKGSKNKSP
  SKAAQKKAEATGEKRPRGRPRKWPQQVVQKKPAQEETEETSSQESAEED
• Function: Functions as a transcriptional regulator. Functions in cell cycle regulation through CCNA2. Plays an important role in chromosome condensation during the meiotic G2/M transition of spermatocytes. Plays a role in postnatal myogenesis, is involved in satellite cell activation. Positively regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.
• KEGG Pathway:
  Transcriptio.l misregulation in cancer (hsa05202)
  MicroR.s in cancer (hsa05206)
• Reactome Pathway: Formation of Senescence-Associated Heterochromatin Foci (SAHF) (R-HSA-2559584)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Silver-Russell syndrome 5	DISUA42K	Strong	Autosomal dominant	[1]
Uterine fibroids	DISBZRMJ	No Known	Unknown	[2]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	High mobility group protein HMGI-C (HMGA2) affects the response to substance of Etoposide.	[34]
Mitomycin	DMH0ZJE	Approved	High mobility group protein HMGI-C (HMGA2) affects the response to substance of Mitomycin.	[34]
Topotecan	DMP6G8T	Approved	High mobility group protein HMGI-C (HMGA2) affects the response to substance of Topotecan.	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of High mobility group protein HMGI-C (HMGA2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of High mobility group protein HMGI-C (HMGA2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of High mobility group protein HMGI-C (HMGA2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of High mobility group protein HMGI-C (HMGA2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of High mobility group protein HMGI-C (HMGA2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of High mobility group protein HMGI-C (HMGA2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of High mobility group protein HMGI-C (HMGA2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of High mobility group protein HMGI-C (HMGA2).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of High mobility group protein HMGI-C (HMGA2).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of High mobility group protein HMGI-C (HMGA2).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of High mobility group protein HMGI-C (HMGA2).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of High mobility group protein HMGI-C (HMGA2).	[15]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of High mobility group protein HMGI-C (HMGA2).	[16]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of High mobility group protein HMGI-C (HMGA2).	[17]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of High mobility group protein HMGI-C (HMGA2).	[18]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of High mobility group protein HMGI-C (HMGA2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of High mobility group protein HMGI-C (HMGA2).	[20]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of High mobility group protein HMGI-C (HMGA2).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of High mobility group protein HMGI-C (HMGA2).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of High mobility group protein HMGI-C (HMGA2).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of High mobility group protein HMGI-C (HMGA2).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of High mobility group protein HMGI-C (HMGA2).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of High mobility group protein HMGI-C (HMGA2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of High mobility group protein HMGI-C (HMGA2).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of High mobility group protein HMGI-C (HMGA2).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of High mobility group protein HMGI-C (HMGA2).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of High mobility group protein HMGI-C (HMGA2).	[28]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of High mobility group protein HMGI-C (HMGA2).	[29]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of High mobility group protein HMGI-C (HMGA2).	[30]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of High mobility group protein HMGI-C (HMGA2).	[31]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of High mobility group protein HMGI-C (HMGA2).	[32]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of High mobility group protein HMGI-C (HMGA2).	[33]

1 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 High mobility group protein HMGI-C (HMGA2).	[11]

References

• [1] Challenges for CNV interpretation in clinical molecular karyotyping: lessons learned from a 1001 sample experience. Eur J Med Genet. 2009 Nov-Dec;52(6):398-403. doi: 10.1016/j.ejmg.2009.09.002. Epub 2009 Sep 16.
• [2] Uterine leiomyomata and decreased height: a common HMGA2 predisposition allele. Hum Genet. 2009 Apr;125(3):257-63. doi: 10.1007/s00439-008-0621-6. Epub 2009 Jan 9.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [10] 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.
• [11] 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.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [15] 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.
• [16] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [17] Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2076-81. doi: 10.1073/pnas.1011936108. Epub 2011 Jan 18.
• [18] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [19] ER stress-enhanced HMGA2 plays an important role in Cr (VI)-induced glycolysis and inhibited oxidative phosphorylation by targeting the transcription of ATF4. Chem Biol Interact. 2023 Jan 5;369:110293. doi: 10.1016/j.cbi.2022.110293. Epub 2022 Dec 5.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [23] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [24] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [25] 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.
• [26] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [27] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [28] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [29] 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.
• [30] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [31] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [32] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [33] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.
• [34] 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.