Details of Drug Off-Target (DOT)

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

• DOT Name: MYND-type zinc finger-containing chromatin reader ZMYND8
• Synonyms: Cutaneous T-cell lymphoma-associated antigen se14-3; CTCL-associated antigen se14-3; Protein kinase C-binding protein 1; Rack7; Transcription coregulator ZMYND8; Zinc finger MYND domain-containing protein 8
• Gene Name: ZMYND8
• Related Disease: Autism spectrum disorder
• UniProt ID: ZMYD8_HUMAN
• PDB ID: 4COS; 5B73; 5MQ4; 5Y1Z; 7CWH
• Pfam ID: PF00439 ; PF12064 ; PF00628 ; PF00855
• Sequence:
  MDISTRSKDPGSAERTAQKRKFPSPPHSSNGHSPQDTSTSPIKKKKKPGLLNSNNKEQSE
  LRHGPFYYMKQPLTTDPVDVVPQDGRNDFYCWVCHREGQVLCCELCPRVYHAKCLRLTSE
  PEGDWFCPECEKITVAECIETQSKAMTMLTIEQLSYLLKFAIQKMKQPGTDAFQKPVPLE
  QHPDYAEYIFHPMDLCTLEKNAKKKMYGCTEAFLADAKWILHNCIIYNGGNHKLTQIAKV
  VIKICEHEMNEIEVCPECYLAACQKRDNWFCEPCSNPHPLVWAKLKGFPFWPAKALRDKD
  GQVDARFFGQHDRAWVPINNCYLMSKEIPFSVKKTKSIFNSAMQEMEVYVENIRRKFGVF
  NYSPFRTPYTPNSQYQMLLDPTNPSAGTAKIDKQEKVKLNFDMTASPKILMSKPVLSGGT
  GRRISLSDMPRSPMSTNSSVHTGSDVEQDAEKKATSSHFSASEESMDFLDKSTASPASTK
  TGQAGSLSGSPKPFSPQLSAPITTKTDKTSTTGSILNLNLDRSKAEMDLKELSESVQQQS
  TPVPLISPKRQIRSRFQLNLDKTIESCKAQLGINEISEDVYTAVEHSDSEDSEKSDSSDS
  EYISDDEQKSKNEPEDTEDKEGCQMDKEPSAVKKKPKPTNPVEIKEELKSTSPASEKADP
  GAVKDKASPEPEKDFSEKAKPSPHPIKDKLKGKDETDSPTVHLGLDSDSESELVIDLGED
  HSGREGRKNKKEPKEPSPKQDVVGKTPPSTTVGSHSPPETPVLTRSSAQTSAAGATATTS
  TSSTVTVTAPAPAATGSPVKKQRPLLPKETAPAVQRVVWNSSSKFQTSSQKWHMQKMQRQ
  QQQQQQQNQQQQPQSSQGTRYQTRQAVKAVQQKEITQSPSTSTITLVTSTQSSPLVTSSG
  SMSTLVSSVNADLPIATASADVAADIAKYTSKMMDAIKGTMTEIYNDLSKNTTGSTIAEI
  RRLRIEIEKLQWLHQQELSEMKHNLELTMAEMRQSLEQERDRLIAEVKKQLELEKQQAVD
  ETKKKQWCANCKKEAIFYCCWNTSYCDYPCQQAHWPEHMKSCTQSATAPQQEADAEVNTE
  TLNKSSQGSSSSTQSAPSETASASKEKETSAEKSKESGSTLDLSGSRETPSSILLGSNQG
  SDHSRSNKSSWSSSDEKRGSTRSDHNTSTSTKSLLPKESRLDTFWD
• Function: Chromatin reader that recognizes dual histone modifications such as histone H3.1 dimethylated at 'Lys-36' and histone H4 acetylated at 'Lys-16' (H3.1K36me2-H4K16ac) and histone H3 methylated at 'Lys-4' and histone H4 acetylated at 'Lys-14' (H3K4me1-H3K14ac). May act as a transcriptional corepressor for KDM5D by recognizing the dual histone signature H3K4me1-H3K14ac. May also act as a transcriptional corepressor for KDM5C and EZH2. Recognizes acetylated histone H4 and recruits the NuRD chromatin remodeling complex to damaged chromatin for transcriptional repression and double-strand break repair by homologous recombination. Also activates transcription elongation by RNA polymerase II through recruiting the P-TEFb complex to target promoters. Localizes to H3.1K36me2-H4K16ac marks at all-trans-retinoic acid (ATRA)-responsive genes and positively regulates their expression. Promotes neuronal differentiation by associating with regulatory regions within the MAPT gene, to enhance transcription of a protein-coding MAPT isoform and suppress the non-coding MAPT213 isoform. Suppresses breast cancer, and prostate cancer cell invasion and metastasis.
• Tissue Specificity: Expressed in neurons (at protein level) . Absent in astrocytes (at protein level) . Expressed in all tissues examined with highest expression in brain, lung, pancreas, and placenta . Expressed in cutaneous T-cell lymphomas (CTCL) .

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[1]

23 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 MYND-type zinc finger-containing chromatin reader ZMYND8.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[12]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[15]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[16]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[17]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[25]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[26]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of MYND-type zinc finger-containing chromatin reader ZMYND8.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of MYND-type zinc finger-containing chromatin reader ZMYND8.	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of MYND-type zinc finger-containing chromatin reader ZMYND8.	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of MYND-type zinc finger-containing chromatin reader ZMYND8.	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of MYND-type zinc finger-containing chromatin reader ZMYND8.	[22]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8. J Biol Chem. 2016 Feb 5;291(6):2664-81. doi: 10.1074/jbc.M115.679985. Epub 2015 Dec 11.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] 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.
• [8] 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.
• [9] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] 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.
• [13] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [14] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [17] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [18] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [19] 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.
• [20] Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16669-74. doi: 10.1073/pnas.1108190108. Epub 2011 Sep 26.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [27] Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.