Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS15WNF)

• DOT Name: Myomegalin (PDE4DIP)
• Synonyms: Cardiomyopathy-associated protein 2; Phosphodiesterase 4D-interacting protein
• Gene Name: PDE4DIP
• Related Disease:
  Esophageal squamous cell carcinoma
  Langer mesomelic dysplasia
  Pineoblastoma
  Squamous cell carcinoma
• UniProt ID: MYOME_HUMAN
• Pfam ID: PF07989 ; PF06758
• Sequence:
  MSNGYRTLSQHLNDLKKENFSLKLRIYFLEERMQQKYEASREDIYKRNIELKVEVESLKR
  ELQDKKQHLDKTWADVENLNSQNEAELRRQFEERQQETEHVYELLENKIQLLQEESRLAK
  NEAARMAALVEAEKECNLELSEKLKGVTKNWEDVPGDQVKPDQYTEALAQRDKRIEELNQ
  SLAAQERLVEQLSREKQQLLHLLEEPTSMEVQPMTEELLKQQKLNSHETTITQQSVSDSH
  LAELQEKIQQTEATNKILQEKLNEMSYELKCAQESSQKQDGTIQNLKETLKSRERETEEL
  YQVIEGQNDTMAKLREMLHQSQLGQLHSSEGTSPAQQQVALLDLQSALFCSQLEIQKLQR
  VVRQKERQLADAKQCVQFVEAAAHESEQQKEASWKHNQELRKALQQLQEELQNKSQQLRA
  WEAEKYNEIRTQEQNIQHLNHSLSHKEQLLQEFRELLQYRDNSDKTLEANEMLLEKLRQR
  IHDKAVALERAIDEKFSALEEKEKELRQLRLAVRERDHDLERLRDVLSSNEATMQSMESL
  LRAKGLEVEQLSTTCQNLQWLKEEMETKFSRWQKEQESIIQQLQTSLHDRNKEVEDLSAT
  LLCKLGPGQSEIAEELCQRLQRKERMLQDLLSDRNKQVLEHEMEIQGLLQSVSTREQESQ
  AAAEKLVQALMERNSELQALRQYLGGRDSLMSQAPISNQQAEVTPTGRLGKQTDQGSMQI
  PSRDDSTSLTAKEDVSIPRSTLGDLDTVAGLEKELSNAKEELELMAKKERESQMELSALQ
  SMMAVQEEELQVQAADMESLTRNIQIKEDLIKDLQMQLVDPEDIPAMERLTQEVLLLREK
  VASVESQGQEISGNRRQQLLLMLEGLVDERSRLNEALQAERQLYSSLVKFHAHPESSERD
  RTLQVELEGAQVLRSRLEEVLGRSLERLNRLETLAAIGGAAAGDDTEDTSTEFTDSIEEE
  AAHHSHQQLVKVALEKSLATVETQNPSFSPPSPMGGDSNRCLQEEMLHLRAEFHQHLEEK
  RKAEEELKELKAQIEEAGFSSVSHIRNTMLSLCLENAELKEQMGEAMSDGWEIEEDKEKG
  EVMVETVVTKEGLSESSLQAEFRKLQGKLKNAHNIINLLKEQLVLSSKEGNSKLTPELLV
  HLTSTIERINTELVGSPGKHQHQEEGNVTVRPFPRPQSLDLGATFTVDAHQLDNQSQPRD
  PGPQSAFSLPGSTQHLRSQLSQCKQRYQDLQEKLLLSEATVFAQANELEKYRVMLTGESL
  VKQDSKQIQVDLQDLGYETCGRSENEAEREETTSPECEEHNSLKEMVLMEGLCSEQGRRG
  STLASSSERKPLENQLGKQEEFRVYGKSENILVLRKDIKDLKAQLQNANKVIQNLKSRVR
  SLSVTSDYSSSLERPRKLRAVGTLEGSSPHSVPDEDEGWLSDGTGAFYSPGLQAKKDLES
  LIQRVSQLEAQLPKNGLEEKLAEELRSASWPGKYDSLIQDQARELSYLRQKIREGRGICY
  LITRHAKDTVKSFEDLLRSNDIDYYLGQSFREQLAQGSQLTERLTSKLSTKDHKSEKDQA
  GLEPLALRLSRELQEKEKVIEVLQAKLDARSLTPSSSHALSDSHRSPSSTSFLSDELEAC
  SDMDIVSEYTHYEEKKASPSHSDSIHHSSHSAVLSSKPSSTSASQGAKAESNSNPISLPT
  PQNTPKEANQAHSGFHFHSIPKLASLPQAPLPSAPSSFLPFSPTGPLLLGCCETPVVSLA
  EAQQELQMLQKQLGESASTVPPASTATLLSNDLEADSSYYLNSAQPHSPPRGTIELGRIL
  EPGYLGSSGKWDVMRPQKGSVSGDLSSGSSVYQLNSKPTGADLLEEHLGEIRNLRQRLEE
  SICINDRLREQLEHRLTSTARGRGSTSNFYSQGLESIPQLCNENRVLREDNRRLQAQLSH
  VSREHSQETESLREALLSSRSHLQELEKELEHQKVERQQLLEDLREKQQEVLHFREERLS
  LQENDSRLQHKLVLLQQQCEEKQQLFESLQSELQIYEALYGNSKKGLKAYSLDACHQIPL
  SSDLSHLVAEVRALRGQLEQSIQGNNCLRLQLQQQLESGAGKASLSPSSINQNFPASTDP
  GNKQLLLQDSAVSPPVRDVGMNSPALVFPSSASSTPGSETPIINRANGLGLDTSPVMKTP
  PKLEGDATDGSFANKHGRHVIGHIDDYSALRQQIAEGKLLVKKIVSLVRSACSFPGLEAQ
  GTEVLGSKGIHELRSSTSALHHALEESASLLTMFWRAALPSTHIPVLPGKVGESTERELL
  ELRTKVSKQERLLQSTTEHLKNANQQKESMEQFIVSQLTRTHDVLKKARTNLEVKSLRAL
  PCTPAL
• Function: Functions as an anchor sequestering components of the cAMP-dependent pathway to Golgi and/or centrosomes; [Isoform 13]: Participates in microtubule dynamics, promoting microtubule assembly. Depending upon the cell context, may act at the level of the Golgi apparatus or that of the centrosome. In complex with AKAP9, recruits CAMSAP2 to the Golgi apparatus and tethers non-centrosomal minus-end microtubules to the Golgi, an important step for polarized cell movement. In complex with AKAP9, EB1/MAPRE1 and CDK5RAP2, contributes to microtubules nucleation and extension from the centrosome to the cell periphery, a crucial process for directed cell migration, mitotic spindle orientation and cell-cycle progression.
• Tissue Specificity: Highly expressed in adult and fetal heart, in skeletal muscle and, to a lower extent, in brain and placenta.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[1]
Langer mesomelic dysplasia	DISCXVK3	Strong	Genetic Variation	[2]
Pineoblastoma	DISQK8F3	Strong	Biomarker	[3]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[1]

3 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 Myomegalin (PDE4DIP).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Myomegalin (PDE4DIP).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Myomegalin (PDE4DIP).	[18]

20 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 Myomegalin (PDE4DIP).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Myomegalin (PDE4DIP).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Myomegalin (PDE4DIP).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myomegalin (PDE4DIP).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Myomegalin (PDE4DIP).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Myomegalin (PDE4DIP).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Myomegalin (PDE4DIP).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Myomegalin (PDE4DIP).	[11]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Myomegalin (PDE4DIP).	[13]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Myomegalin (PDE4DIP).	[14]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Myomegalin (PDE4DIP).	[15]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine increases the expression of Myomegalin (PDE4DIP).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Myomegalin (PDE4DIP).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Myomegalin (PDE4DIP).	[17]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Myomegalin (PDE4DIP).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Myomegalin (PDE4DIP).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Myomegalin (PDE4DIP).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Myomegalin (PDE4DIP).	[22]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Myomegalin (PDE4DIP).	[23]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of Myomegalin (PDE4DIP).	[24]

References

• [1] Serum anti-myomegalin antibodies in patients with esophageal squamous cell carcinoma.Int J Oncol. 2007 Jan;30(1):97-103.
• [2] Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases.J Thorac Oncol. 2018 Jul;13(7):1022-1027. doi: 10.1016/j.jtho.2018.03.018. Epub 2018 Mar 29.
• [3] Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma.Nat Commun. 2018 Jul 20;9(1):2868. doi: 10.1038/s41467-018-05029-3.
• [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] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [13] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [14] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [15] Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology. 2006 Oct;31(10):2304-12. doi: 10.1038/sj.npp.1301089. Epub 2006 May 3.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [19] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [20] DON shares a similar mode of action as the ribotoxic stress inducer anisomycin while TBTO shares ER stress patterns with the ER stress inducer thapsigargin based on comparative gene expression profiling in Jurkat T cells. Toxicol Lett. 2014 Jan 30;224(3):395-406. doi: 10.1016/j.toxlet.2013.11.005. Epub 2013 Nov 15.
• [21] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [22] 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.
• [23] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [24] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.