Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI8VMHZ)

• DOT Name: 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C)
• Synonyms: EC 3.1.4.53; DPDE1; PDE21; cAMP-specific phosphodiesterase 4C
• Gene Name: PDE4C
• UniProt ID: PDE4C_HUMAN
• PDB ID: 2QYM
• EC Number: 3.1.4.53
• Pfam ID: PF18100 ; PF00233
• Sequence:
  MENLGVGEGAEACSRLSRSRGRHSMTRAPKHLWRQPRRPIRIQQRFYSDPDKSAGCRERD
  LSPRPELRKSRLSWPVSSCRRFDLENGLSCGRRALDPQSSPGLGRIMQAPVPHSQRRESF
  LYRSDSDYELSPKAMSRNSSVASDLHGEDMIVTPFAQVLASLRTVRSNVAALARQQCLGA
  AKQGPVGNPSSSNQLPPAEDTGQKLALETLDELDWCLDQLETLQTRHSVGEMASNKFKRI
  LNRELTHLSETSRSGNQVSEYISRTFLDQQTEVELPKVTAEEAPQPMSRISGLHGLCHSA
  SLSSATVPRFGVQTDQEEQLAKELEDTNKWGLDVFKVAELSGNRPLTAIIFSIFQERDLL
  KTFQIPADTLATYLLMLEGHYHANVAYHNSLHAADVAQSTHVLLATPALEAVFTDLEILA
  ALFASAIHDVDHPGVSNQFLINTNSELALMYNDASVLENHHLAVGFKLLQAENCDIFQNL
  SAKQRLSLRRMVIDMVLATDMSKHMNLLADLKTMVETKKVTSLGVLLLDNYSDRIQVLQN
  LVHCADLSNPTKPLPLYRQWTDRIMAEFFQQGDRERESGLDISPMCDKHTASVEKSQVGF
  IDYIAHPLWETWADLVHPDAQDLLDTLEDNREWYQSKIPRSPSDLTNPERDGPDRFQFEL
  TLEEAEEEDEEEEEEGEETALAKEALELPDTELLSPEAGPDPGDLPLDNQRT
• Function: Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
• Tissue Specificity: Expressed in various tissues but not in cells of the immune system.
• 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

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 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[10]
Roflumilast	DMPGHY8	Approved	Roflumilast decreases the activity of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[11]
Cilomilast	DMHSM7I	Discontinued in Phase 3	Cilomilast decreases the activity of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[13]
Trequinsin	DMQRSMD	Terminated	Trequinsin decreases the activity of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C).	[16]

References

• [1] 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.
• [2] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Identification of transcriptional biomarkers induced by SERMS in human endometrial cells using multivariate analysis of DNA microarrays. Biomarkers. 2004 Nov-Dec;9(6):447-60.
• [6] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [15] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.