Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB1QT9U)

• DOT Name: HMG domain-containing protein 4 (HMGXB4)
• Synonyms: HMG box-containing protein 4; High mobility group protein 2-like 1; Protein HMGBCG
• Gene Name: HMGXB4
• Related Disease:
  Bipolar disorder
  Primary myelofibrosis
• UniProt ID: HMGX4_HUMAN
• Pfam ID: PF13775 ; PF00505
• Sequence:
  MAYDDSVKKEDCFDGDHTFEDIGLAAGRSQREKKRSYKDFLREEEEIAAQVRNSSKKKLK
  DSELYFLGTDTHKKKRKHSSDDYYYGDISSLESSQKKKKKSSPQSTDTAMDLLKAITSPL
  AAGSKPSKKTGEKSSGSSSHSESKKEHHRKKVSGSSGELPLEDGGSHKSKKMKPLYVNTE
  TLTLREPDGLKMKLILSPKEKGSSSVDEESFQYPSQQATVKKSSKKSARDEQGALLLGHE
  LQSFLKTARKKHKSSSDAHSSPGPEGCGSDASQFAESHSANLDLSGLEPILVESDSSSGG
  ELEAGELVIDDSYREIKKKKKSKKSKKKKDKEKHKEKRHSKSKRSLGLSAVPVGEVTVTS
  GPPPSIPYAGAAAPPLPLPGLHTDGHSEKKKKKEEKDKERERGEKPKKKNMSAYQVFCKE
  YRVTIVADHPGIDFGELSKKLAEVWKQLPEKDKLIWKQKAQYLQHKQNKAEATTVKRKAS
  SSEGSMKVKASSVGVLSPQKKSPPTTMLLPASPAKAPETEPIDVAAHLQLLGESLSLIGH
  RLQETEGMVAVSGSLSVLLDSIICALGPLACLTTQLPELNGCPKQVLSNTLDNIAYIMPG
  L
• Function: Negatively regulates Wnt/beta-catenin signaling during development.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[1]
Primary myelofibrosis	DIS6L0CN	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of HMG domain-containing protein 4 (HMGXB4).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of HMG domain-containing protein 4 (HMGXB4).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of HMG domain-containing protein 4 (HMGXB4).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of HMG domain-containing protein 4 (HMGXB4).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of HMG domain-containing protein 4 (HMGXB4).	[12]

9 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 HMG domain-containing protein 4 (HMGXB4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of HMG domain-containing protein 4 (HMGXB4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of HMG domain-containing protein 4 (HMGXB4).	[6]
Selenium	DM25CGV	Approved	Selenium decreases the expression of HMG domain-containing protein 4 (HMGXB4).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of HMG domain-containing protein 4 (HMGXB4).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of HMG domain-containing protein 4 (HMGXB4).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of HMG domain-containing protein 4 (HMGXB4).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of HMG domain-containing protein 4 (HMGXB4).	[13]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of HMG domain-containing protein 4 (HMGXB4).	[14]

References

• [1] Gene-based SNP mapping of a psychotic bipolar affective disorder linkage region on 22q12.3: association with HMG2L1 and TOM1.Am J Med Genet B Neuropsychiatr Genet. 2008 Jan 5;147B(1):59-67. doi: 10.1002/ajmg.b.30574.
• [2] Integrative analysis of copy number and gene expression data suggests novel pathogenetic mechanisms in primary myelofibrosis.Int J Cancer. 2016 Apr 1;138(7):1657-69. doi: 10.1002/ijc.29920. Epub 2015 Nov 25.
• [3] 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.
• [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] 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] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [9] 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.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] 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.
• [13] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [14] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.