Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKY12D9)

• DOT Name: Putative histone-lysine N-methyltransferase PRDM6 (PRDM6)
• Synonyms: EC 2.1.1.361; PR domain zinc finger protein 6; PR domain-containing protein 6
• Gene Name: PRDM6
• Related Disease:
  Delirium
  Parkinson disease
  Acute myelogenous leukaemia
  Alzheimer disease
  Anxiety
  Anxiety disorder
  Breast carcinoma
  Cardiovascular disease
  Classic phenylketonuria
  Euthyroid goiter
  Gastroesophageal reflux disease
  Hepatitis C virus infection
  Hypertrophic cardiomyopathy
  Irritable bowel syndrome
  Long QT syndrome
  Neoplasm
  Obesity
  Osteoporosis
  Prostate cancer
  Prostate carcinoma
  Coronary heart disease
  Patent ductus arteriosus
  Obsolete familial patent arterial duct
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Advanced cancer
  Alopecia
  Ebola virus infection
  Non-insulin dependent diabetes
  Patent ductus arteriosus 3
  Phenylketonuria
  Type-1 diabetes
• UniProt ID: PRDM6_HUMAN
• EC Number: 2.1.1.361
• Pfam ID: PF21549 ; PF00096
• Sequence:
  MLKPGDPGGSAFLKVDPAYLQHWQQLFPHGGAGPLKGSGAAGLLSAPQPLQPPPPPPPPE
  RAEPPPDSLRPRPASLSSASSTPASSSTSASSASSCAAAAAAAALAGLSALPVSQLPVFA
  PLAAAAVAAEPLPPKELCLGATSGPGPVKCGGGGGGGGEGRGAPRFRCSAEELDYYLYGQ
  QRMEIIPLNQHTSDPNNRCDMCADNRNGECPMHGPLHSLRRLVGTSSAAAAAPPPELPEW
  LRDLPREVCLCTSTVPGLAYGICAAQRIQQGTWIGPFQGVLLPPEKVQAGAVRNTQHLWE
  IYDQDGTLQHFIDGGEPSKSSWMRYIRCARHCGEQNLTVVQYRSNIFYRACIDIPRGTEL
  LVWYNDSYTSFFGIPLQCIAQDENLNVPSTVMEAMCRQDALQPFNKSSKLAPTTQQRSVV
  FPQTPCSRNFSLLDKSGPIESGFNQINVKNQRVLASPTSTSQLHSEFSDWHLWKCGQCFK
  TFTQRILLQMHVCTQNPDRPYQCGHCSQSFSQPSELRNHVVTHSSDRPFKCGYCGRAFAG
  ATTLNNHIRTHTGEKPFKCERCERSFTQATQLSRHQRMPNECKPITESPESIEVD
• Function: Putative histone methyltransferase that acts as a transcriptional repressor of smooth muscle gene expression. Promotes the transition from differentiated to proliferative smooth muscle by suppressing differentiation and maintaining the proliferative potential of vascular smooth muscle cells. Also plays a role in endothelial cells by inhibiting endothelial cell proliferation, survival and differentiation. It is unclear whether it has histone methyltransferase activity in vivo. According to some authors, it does not act as a histone methyltransferase by itself and represses transcription by recruiting EHMT2/G9a. According to others, it possesses histone methyltransferase activity when associated with other proteins and specifically methylates 'Lys-20' of histone H4 in vitro. 'Lys-20' methylation represents a specific tag for epigenetic transcriptional repression.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:HS00755-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Delirium	DIS2OKP1	Definitive	Genetic Variation	[1]
Parkinson disease	DISQVHKL	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Anxiety	DISIJDBA	Strong	Genetic Variation	[5]
Anxiety disorder	DISBI2BT	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[7]
Classic phenylketonuria	DISLU64N	Strong	Altered Expression	[8]
Euthyroid goiter	DISLRPYJ	Strong	Genetic Variation	[9]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Biomarker	[10]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[11]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[12]
Irritable bowel syndrome	DIS27206	Strong	Genetic Variation	[5]
Long QT syndrome	DISMKWS3	Strong	Genetic Variation	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Strong	Genetic Variation	[13]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[13]
Prostate cancer	DISF190Y	Strong	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[14]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[15]
Patent ductus arteriosus	DIS9P8YS	moderate	Genetic Variation	[16]
Obsolete familial patent arterial duct	DISUZERZ	Supportive	Autosomal dominant	[16]
Thyroid cancer	DIS3VLDH	Disputed	Biomarker	[17]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Biomarker	[17]
Thyroid tumor	DISLVKMD	Disputed	Biomarker	[17]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[18]
Alopecia	DIS37HU4	Limited	Genetic Variation	[19]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[20]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[21]
Patent ductus arteriosus 3	DISFCC43	Limited	Autosomal dominant	[16]
Phenylketonuria	DISCU56J	Limited	Biomarker	[22]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[23]

4 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 Putative histone-lysine N-methyltransferase PRDM6 (PRDM6).	[24]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Putative histone-lysine N-methyltransferase PRDM6 (PRDM6).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Putative histone-lysine N-methyltransferase PRDM6 (PRDM6).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Putative histone-lysine N-methyltransferase PRDM6 (PRDM6).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Putative histone-lysine N-methyltransferase PRDM6 (PRDM6).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Putative histone-lysine N-methyltransferase PRDM6 (PRDM6).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Putative histone-lysine N-methyltransferase PRDM6 (PRDM6).	[29]

References

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• [2] L-dopa co-drugs in nanostructured lipid carriers: A comparative study.Mater Sci Eng C Mater Biol Appl. 2017 Mar 1;72:168-176. doi: 10.1016/j.msec.2016.11.060. Epub 2016 Nov 18.
• [3] PRISM: methylation pattern-based, reference-free inference of subclonal makeup.Bioinformatics. 2019 Jul 15;35(14):i520-i529. doi: 10.1093/bioinformatics/btz327.
• [4] Relating constructs of attention and working memory to social withdrawal in Alzheimer's disease and schizophrenia: issues regarding paradigm selection.Neurosci Biobehav Rev. 2019 Feb;97:47-69. doi: 10.1016/j.neubiorev.2018.09.025. Epub 2018 Nov 3.
• [5] A Measure of Suffering in relation to Anxiety and Quality of Life in IBS Patients: Preliminary Results.Biomed Res Int. 2017;2017:2387681. doi: 10.1155/2017/2387681. Epub 2017 Jul 4.
• [6] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [7] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [8] Pegvaliase: First Global Approval.BioDrugs. 2018 Aug;32(4):391-395. doi: 10.1007/s40259-018-0292-3.
• [9] Analysis of correlation between the process of thyroid fibrosis and TGFB1 gene expression level in fine-needle aspiration biopsy (FNAB) thyroid specimens collected from patients with Hashimoto's thyroiditis and non-toxic goitre.Exp Clin Endocrinol Diabetes. 2010 Jul;118(7):420-6. doi: 10.1055/s-0029-1225614. Epub 2010 Feb 26.
• [10] PRISM, a Patient-Reported Outcome Instrument, Accurately Measures Symptom Change in Refractory Gastroesophageal Reflux Disease.Dig Dis Sci. 2017 Mar;62(3):593-606. doi: 10.1007/s10620-016-4440-7. Epub 2017 Jan 23.
• [11] Anti-HCV immunoblot indeterminate results in blood donors: non-specific reactivity or past exposure to HCV?.Vox Sang. 2017 Aug;112(6):542-548. doi: 10.1111/vox.12547.
• [12] High-throughput single-strand conformation polymorphism analysis by automated capillary electrophoresis: robust multiplex analysis and pattern-based identification of allelic variants.Hum Mutat. 1999;13(4):318-27. doi: 10.1002/(SICI)1098-1004(1999)13:4<318::AID-HUMU9>3.0.CO;2-F.
• [13] Identification of Novel Potentially Pleiotropic Variants Associated With Osteoporosis and Obesity Using the cFDR Method.J Clin Endocrinol Metab. 2018 Jan 1;103(1):125-138. doi: 10.1210/jc.2017-01531.
• [14] Quantification of mutant SPOP proteins in prostate cancer using mass spectrometry-based targeted proteomics.J Transl Med. 2017 Aug 15;15(1):175. doi: 10.1186/s12967-017-1276-7.
• [15] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [16] Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus. Am J Hum Genet. 2016 Jun 2;98(6):1082-1091. doi: 10.1016/j.ajhg.2016.03.022. Epub 2016 May 12.
• [17] Pictorial Representation of Illness and Self Measure-Revised 2 (PRISM-R2): an effective tool to assess perceived burden of thyroid cancer in mainland China.Support Care Cancer. 2018 Sep;26(9):3267-3275. doi: 10.1007/s00520-018-4172-7. Epub 2018 Apr 11.
• [18] High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.Nat Biotechnol. 2016 Apr;34(4):419-23. doi: 10.1038/nbt.3460. Epub 2016 Feb 29.
• [19] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [20] Development and evaluation of a fluorogenic 5' nuclease assay to detect and differentiate between Ebola virus subtypes Zaire and Sudan.J Clin Microbiol. 2001 Nov;39(11):4125-30. doi: 10.1128/JCM.39.11.4125-4130.2001.
• [21] The rs7204609 polymorphism in the fat mass and obesity-associated gene is positively associated with central obesity and microalbuminuria in patients with type 2 diabetes from Southern Brazil.J Ren Nutr. 2012 Mar;22(2):228-236. doi: 10.1053/j.jrn.2011.03.004. Epub 2011 Jul 13.
• [22] Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial.Mol Genet Metab. 2018 May;124(1):20-26. doi: 10.1016/j.ymgme.2018.03.003. Epub 2018 Mar 18.
• [23] CTLA-4 CT60 polymorphism in thyroid and polyglandular autoimmunity.Horm Metab Res. 2009 Jun;41(6):426-9. doi: 10.1055/s-0029-1214414.
• [24] 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.
• [25] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.