Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1GI1TE)

• DOT Name: cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B)
• Synonyms: EC 3.1.4.17; CGIPDE1; CGIP1; Cyclic GMP-inhibited phosphodiesterase B; CGI-PDE B
• Gene Name: PDE3B
• UniProt ID: PDE3B_HUMAN
• PDB ID: 1SO2; 1SOJ
• EC Number: 3.1.4.17
• Pfam ID: PF00233
• Sequence:
  MRRDERDAKAMRSLQPPDGAGSPPESLRNGYVKSCVSPLRQDPPRGFFFHLCRFCNVELR
  PPPASPQQPRRCSPFCRARLSLGALAAFVLALLLGAEPESWAAGAAWLRTLLSVCSHSLS
  PLFSIACAFFFLTCFLTRTKRGPGPGRSCGSWWLLALPACCYLGDFLVWQWWSWPWGDGD
  AGSAAPHTPPEAAAGRLLLVLSCVGLLLTLAHPLRLRHCVLVLLLASFVWWVSFTSLGSL
  PSALRPLLSGLVGGAGCLLALGLDHFFQIREAPLHPRLSSAAEEKVPVIRPRRRSSCVSL
  GETAASYYGSCKIFRRPSLPCISREQMILWDWDLKQWYKPHYQNSGGGNGVDLSVLNEAR
  NMVSDLLTDPSLPPQVISSLRSISSLMGAFSGSCRPKINPLTPFPGFYPCSEIEDPAEKG
  DRKLNKGLNRNSLPTPQLRRSSGTSGLLPVEQSSRWDRNNGKRPHQEFGISSQGCYLNGP
  FNSNLLTIPKQRSSSVSLTHHVGLRRAGVLSSLSPVNSSNHGPVSTGSLTNRSPIEFPDT
  ADFLNKPSVILQRSLGNAPNTPDFYQQLRNSDSNLCNSCGHQMLKYVSTSESDGTDCCSG
  KSGEEENIFSKESFKLMETQQEEETEKKDSRKLFQEGDKWLTEEAQSEQQTNIEQEVSLD
  LILVEEYDSLIEKMSNWNFPIFELVEKMGEKSGRILSQVMYTLFQDTGLLEIFKIPTQQF
  MNYFRALENGYRDIPYHNRIHATDVLHAVWYLTTRPVPGLQQIHNGCGTGNETDSDGRIN
  HGRIAYISSKSCSNPDESYGCLSSNIPALELMALYVAAAMHDYDHPGRTNAFLVATNAPQ
  AVLYNDRSVLENHHAASAWNLYLSRPEYNFLLHLDHVEFKRFRFLVIEAILATDLKKHFD
  FLAEFNAKANDVNSNGIEWSNENDRLLVCQVCIKLADINGPAKVRDLHLKWTEGIVNEFY
  EQGDEEANLGLPISPFMDRSSPQLAKLQESFITHIVGPLCNSYDAAGLLPGQWLEAEEDN
  DTESGDDEDGEELDTEDEEMENNLNPKPPRRKSRRRIFCQLMHHLTENHKIWKEIVEEEE
  KCKADGNKLQVENSSLPQADEIQVIEEADEEE
• Function: Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological process. Regulates angiogenesis by inhibiting the cAMP-dependent guanine nucleotide exchange factor RAPGEF3 and downstream phosphatidylinositol 3-kinase gamma-mediated signaling. Controls cardiac contractility by reducing cAMP concentration in cardiocytes.
• Tissue Specificity: Abundant in adipose tissues.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Apelin sig.ling pathway (hsa04371)
  Insulin sig.ling pathway (hsa04910)
  Progesterone-mediated oocyte maturation (hsa04914)
  Glucagon sig.ling pathway (hsa04922)
  Regulation of lipolysis in adipocytes (hsa04923)
  Renin secretion (hsa04924)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  PDE3B signalling (R-HSA-165160)

Molecular Interaction Atlas (MIA) of This DOT

4 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 cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[11]

12 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 cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[4]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[5]
Roflumilast	DMPGHY8	Approved	Roflumilast decreases the activity of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[10]
Trequinsin	DMQRSMD	Terminated	Trequinsin decreases the activity of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[13]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[14]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B).	[15]

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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro: estrogen receptor dependent or independent pathways of raloxifene. J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):281-9.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [15] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.