Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZQOG9A)

• DOT Name: Hyaluronan and proteoglycan link protein 4 (HAPLN4)
• Synonyms: Brain link protein 2
• Gene Name: HAPLN4
• Related Disease:
  Glioma
  Neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Schizophrenia
• UniProt ID: HPLN4_HUMAN
• Pfam ID: PF07686 ; PF00193
• Sequence:
  MVCARAALGPGALWAAAWGVLLLTAPAGAQRGRKKVVHVLEGESGSVVVQTAPGQVVSHR
  GGTIVLPCRYHYEAAAHGHDGVRLKWTKVVDPLAFTDVFVALGPQHRAFGSYRGRAELQG
  DGPGDASLVLRNVTLQDYGRYECEVTNELEDDAGMVKLDLEGVVFPYHPRGGRYKLTFAE
  AQRACAEQDGILASAEQLHAAWRDGLDWCNAGWLRDGSVQYPVNRPREPCGGLGGTGSAG
  GGGDANGGLRNYGYRHNAEERYDAFCFTSNLPGRVFFLKPLRPVPFSGAARACAARGAAV
  AKVGQLFAAWKLQLLDRCTAGWLADGSARYPIVNPRARCGGRRPGVRSLGFPDATRRLFG
  VYCYRAPGAPDPAPGGWGWGWAGGGGWAGGARDPAAWTPLHV
• Function: Essential for the proper localization of brevican (BCAN), mainly as a perineuronal nets (PNNs)-type deposition in the brainstem and cerebellum thereby playing a key role in the formation and structural organization of PNNs. Contributes to the formation and transmission of inhibitory GABAergic synapses between Purkinje cells and deep cerebellar nuclei neurons.
• Tissue Specificity: Expressed predominantly in brain.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]

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 Hyaluronan and proteoglycan link protein 4 (HAPLN4).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Hyaluronan and proteoglycan link protein 4 (HAPLN4).	[9]

6 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 Hyaluronan and proteoglycan link protein 4 (HAPLN4).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Hyaluronan and proteoglycan link protein 4 (HAPLN4).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Hyaluronan and proteoglycan link protein 4 (HAPLN4).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Hyaluronan and proteoglycan link protein 4 (HAPLN4).	[8]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Hyaluronan and proteoglycan link protein 4 (HAPLN4).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Hyaluronan and proteoglycan link protein 4 (HAPLN4).	[10]

References

• [1] Reduced expression of the hyaluronan and proteoglycan link proteins in malignant gliomas.J Biol Chem. 2009 Sep 25;284(39):26547-56. doi: 10.1074/jbc.M109.013185. Epub 2009 Jul 24.
• [2] A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.Nat Genet. 2018 Jul;50(7):968-978. doi: 10.1038/s41588-018-0132-x. Epub 2018 Jun 18.
• [3] Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia: B3GAT2 is associated with disease risk and cortical surface area.Biol Psychiatry. 2011 Jan 1;69(1):90-6. doi: 10.1016/j.biopsych.2010.07.035. Epub 2010 Oct 15.
• [4] 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.
• [5] 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.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] 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.