Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1RWFV0)

• DOT Name: 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D)
• Synonyms: EC 3.1.4.53; DPDE3; PDE43; cAMP-specific phosphodiesterase 4D
• Gene Name: PDE4D
• Related Disease:
  Acrodysostosis 1 with or without hormone resistance
  Acrodysostosis 2 with or without hormone resistance
  Acrodysostosis
  Chromosome 5q12 deletion syndrome
  Obsolete acrodysostosis with multiple hormone resistance
• UniProt ID: PDE4D_HUMAN
• PDB ID: 1E9K ; 1MKD ; 1OYN ; 1PTW ; 1Q9M ; 1TB7 ; 1TBB ; 1XOM ; 1XON ; 1XOQ ; 1XOR ; 1Y2B ; 1Y2C ; 1Y2D ; 1Y2E ; 1Y2K ; 1ZKN ; 2FM0 ; 2FM5 ; 2PW3 ; 2QYN ; 3G4G ; 3G4I ; 3G4K ; 3G4L ; 3G58 ; 3IAD ; 3IAK ; 3K4S ; 3SL3 ; 3SL4 ; 3SL5 ; 3SL6 ; 3SL8 ; 3V9B ; 4OGB ; 4W1O ; 4WCU ; 5K1I ; 5K32 ; 5LBO ; 5TKB ; 5WH5 ; 5WH6 ; 5WQA ; 6AKR ; 6BOJ ; 6F6U ; 6F8R ; 6F8T ; 6F8U ; 6F8V ; 6F8W ; 6F8X ; 6FDC ; 6FDI ; 6FE7 ; 6FEB ; 6FET ; 6FT0 ; 6FTA ; 6FTW ; 6FW3 ; 6HWO ; 6IAG ; 6IBF ; 6IM6 ; 6IMB ; 6IMD ; 6IMI ; 6IMO ; 6IMR ; 6IMT ; 6IND ; 6INK ; 6INM ; 6KJZ ; 6KK0 ; 6LRM ; 6NJH ; 6NJI ; 6NJJ ; 6RCW ; 6ZBA ; 7A8Q ; 7A9V ; 7AAG ; 7AB9 ; 7ABD ; 7ABE ; 7ABJ ; 7AY6 ; 7B9H ; 7CBJ ; 7CBQ ; 7F2K ; 7F2L ; 7F2M ; 7W4X ; 7W4Y ; 7XAA ; 7XAB ; 7XBB ; 7YQF ; 7YSX ; 8K4C ; 8K4H ; 8W4Q ; 8W4R
• EC Number: 3.1.4.53
• Pfam ID: PF18100 ; PF00233
• Sequence:
  MEAEGSSAPARAGSGEGSDSAGGATLKAPKHLWRHEQHHQYPLRQPQFRLLHPHHHLPPP
  PPPSPQPQPQCPLQPPPPPPLPPPPPPPGAARGRYASSGATGRVRHRGYSDTERYLYCRA
  MDRTSYAVETGHRPGLKKSRMSWPSSFQGLRRFDVDNGTSAGRSPLDPMTSPGSGLILQA
  NFVHSQRRESFLYRSDSDYDLSPKSMSRNSSIASDIHGDDLIVTPFAQVLASLRTVRNNF
  AALTNLQDRAPSKRSPMCNQPSINKATITEEAYQKLASETLEELDWCLDQLETLQTRHSV
  SEMASNKFKRMLNRELTHLSEMSRSGNQVSEFISNTFLDKQHEVEIPSPTQKEKEKKKRP
  MSQISGVKKLMHSSSLTNSSIPRFGVKTEQEDVLAKELEDVNKWGLHVFRIAELSGNRPL
  TVIMHTIFQERDLLKTFKIPVDTLITYLMTLEDHYHADVAYHNNIHAADVVQSTHVLLST
  PALEAVFTDLEILAAIFASAIHDVDHPGVSNQFLINTNSELALMYNDSSVLENHHLAVGF
  KLLQEENCDIFQNLTKKQRQSLRKMVIDIVLATDMSKHMNLLADLKTMVETKKVTSSGVL
  LLDNYSDRIQVLQNMVHCADLSNPTKPLQLYRQWTDRIMEEFFRQGDRERERGMEISPMC
  DKHNASVEKSQVGFIDYIVHPLWETWADLVHPDAQDILDTLEDNREWYQSTIPQSPSPAP
  DDPEEGRQGQTEKFQFELTLEEDGESDTEKDSGSQVEEDTSCSDSKTLCTQDSESTEIPL
  DEQVEEEAVGEEEESQPEACVIDDRSPDT
• Function: Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
• Tissue Specificity: Expressed in colonic epithelial cells (at protein level). Widespread; most abundant in skeletal muscle.; [Isoform 6]: Detected in brain.; [Isoform 8]: Detected in brain, placenta, lung and kidney.; [Isoform 7]: Detected in heart and skeletal muscle.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  cAMP sig.ling pathway (hsa04024)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  DARPP-32 events (R-HSA-180024)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acrodysostosis 1 with or without hormone resistance	DISMLLJ7	Definitive	Autosomal dominant	[1]
Acrodysostosis 2 with or without hormone resistance	DIS6N0DS	Strong	Autosomal dominant	[2]
Acrodysostosis	DISSV94Z	Supportive	Autosomal dominant	[1]
Chromosome 5q12 deletion syndrome	DISIYKUH	Supportive	Unknown	[3]
Obsolete acrodysostosis with multiple hormone resistance	DIS6U70H	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D) increases the Neutropenia ADR of Gemcitabine.	[30]
Mitoxantrone	DMM39BF	Approved	3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D) affects the response to substance of Mitoxantrone.	[31]
Methamphetamine	DMPM4SK	Approved	3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D) affects the response to substance of Methamphetamine.	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[14]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[16]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[17]
Roflumilast	DMPGHY8	Approved	Roflumilast decreases the activity of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[18]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[22]
Cilomilast	DMHSM7I	Discontinued in Phase 3	Cilomilast decreases the activity of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[23]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[24]
Trequinsin	DMQRSMD	Terminated	Trequinsin decreases the activity of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[27]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of 3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D).	[28]

References

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• [2] Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis. Hum Mutat. 2013 Jan;34(1):97-102. doi: 10.1002/humu.22222. Epub 2012 Nov 9.
• [3] Different mutations in PDE4D associated with developmental disorders with mirror phenotypes. J Med Genet. 2014 Jan;51(1):45-54. doi: 10.1136/jmedgenet-2013-101937. Epub 2013 Nov 7.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] 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.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [13] 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.
• [14] 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.
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• [17] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [18] Dynamic activation of cystic fibrosis transmembrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors. J Pharmacol Exp Ther. 2005 Aug;314(2):846-54. doi: 10.1124/jpet.105.083519. Epub 2005 May 18.
• [19] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [20] 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.
• [21] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] Pharmacological profile of a novel phosphodiesterase 4 inhibitor, 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171), a 1,7-naphthyridine derivative, with anti-inflammatory activities. J Pharmacol Exp Ther. 2002 Apr;301(1):241-8. doi: 10.1124/jpet.301.1.241.
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• [25] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [26] 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.
• [27] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [28] 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.
• [29] Differential expression of genes coding for EGF-like factors and ADAMTS1 following gonadotropin stimulation in normal and transformed human granulosa cells. Biochem Biophys Res Commun. 2005 Aug 5;333(3):935-43. doi: 10.1016/j.bbrc.2005.04.177.
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• [31] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [32] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.