phosphodiesterase 4D | Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs) | IUPHAR Guide to IMMUNOPHARMACOLOGY

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phosphodiesterase 4D

  Target has curated data in GtoImmuPdb

Target id: 1303

Nomenclature: phosphodiesterase 4D

Abbreviated Name: PDE4D

Family: Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs)

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - - PDE4D phosphodiesterase 4D
Mouse - - Pde4d phosphodiesterase 4D, cAMP specific
Rat - - Pde4d phosphodiesterase 4D
Previous and Unofficial Names
phosphodiesterase E3 dunce homolog (Drosophila) | cAMP-specific 3',5'-cyclic phosphodiesterase 4D | phosphodiesterase 4D, cAMP specific | phosphodiesterase 4D, cAMP-specific
Database Links
BRENDA 3.1.4.17
CATH/Gene3D 1.10.1300.10
ChEMBL Target CHEMBL288 (Hs), CHEMBL2712 (Rn)
DrugBank Target Q08499 (Hs)
Ensembl Gene ENSG00000113448 (Hs), ENSMUSG00000074661 (Mm), ENSMUSG00000021699 (Mm)
Entrez Gene 5144 (Hs), 238871 (Mm), 24627 (Rn)
Human Protein Atlas ENSG00000113448 (Hs)
KEGG Enzyme 3.1.4.17
KEGG Gene hsa:5144 (Hs), mmu:238871 (Mm), rno:24627 (Rn)
OMIM 600129 (Hs)
Pharos Q08499 (Hs)
SynPHARM 13768 (in complex with Ro20-1724)
13769 (in complex with rolipram)
78414 (in complex with RS-25344)
UniProtKB Q08499 (Hs), Q01063 (Mm), P14270 (Rn)
Wikipedia PDE4D (Hs)
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of the PDE4D Catalytic Domain and UCR2 Regulatory Helix with BPN14770
PDB Id:  6NJJ
Ligand:  BPN14770
Resolution:  2.3Å
Species:  Human
References:  2
Enzyme Reaction
EC Number: 3.1.4.17
Activator (Human)
PKA-mediated phosphorylation  [4]
Rank order of affinity (Human)
cyclic AMP >> cyclic GMP

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CDP840 Hs Inhibition 8.1 pKi 8
⤷ pKi 8.1 (Ki 7.1x10-9 M) [8]
Description: Inhibition of [3H]-R-rolipram binding to recombinant human PDE4D3 isoenzyme
MK-0359 Hs Inhibition 8.9 pIC50 5
⤷ pIC50 8.9 (IC50 1.2x10-9 M) [5]
RS-25344 Hs Inhibition 8.4 pIC50 9
⤷ pIC50 8.4 [9]
apremilast Hs Inhibition 7.5 pIC50 10
⤷ pIC50 7.5 (IC50 3.3x10-8 M) [10]
Description: Potency against recombinant human PDE4D2 isoform in a TR-FRET assay.
compound 29 [Moslin et al., 2017] Hs Inhibition 7.4 pIC50 6
⤷ pIC50 7.4 (IC50 4.3x10-8 M) [6]
Description: Binding affinity calculated be measuring displacement of [3H]cAMP binding to purified recombinant His-Tb-hPDE4D2.
difamilast Hs Inhibition >7.3 pIC50 7
⤷ pIC50 >7.3 (IC50 <5x10-8 M) [7]
Description: Measuring inhibition of substrate hydrolysis by the PDE4D3 isoform.
rolipram Hs Inhibition 7.2 pIC50 12
⤷ pIC50 7.2 (IC50 6.31x10-8 M) [12]
PDE4 inhibitor 16 Hs Inhibition 6.6 pIC50 13
⤷ pIC50 6.6 (IC50 2.4x10-7 M) [13]
Description: Inhibition of enzymatic activity of the recombinant human PDE4D catalytic domain in vitro.
Ro20-1724 Hs Inhibition 6.2 pIC50 12
⤷ pIC50 6.2 (IC50 6.31x10-7 M) [12]
CBS-3595 Hs Inhibition 6.1 pIC50 1
⤷ pIC50 6.1 (IC50 8x10-7 M) [1]
Description: Determined against the PDE4D3 splice variant.
UFM24 Hs Inhibition 5.4 pIC50 11
⤷ pIC50 5.4 (IC50 3.53x10-6 M) [11]
Description: Inhibition of PDE4D2 activity in vitro.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BPN14770 Hs Negative 6.0 – 8.1 pIC50 2
⤷ pIC50 8.1 (IC50 7.4x10-9 M) [2]
Description: Inhibition of a fluorescent determination of reaction rate of cAMP hydrolysis by purified human PDE4D3-S54D dimer (activated).
pIC50 8.1 (IC50 7.8x10-9 M) [2]
Description: Inhibition of a fluorescent determination of reaction rate of cAMP hydrolysis by purified human PDE4D7-S129D dimer (activated).
pIC50 6.9 (IC50 1.27x10-7 M) [2]
Description: Inhibition of a fluorescent determination of reaction rate of cAMP hydrolysis by purified human PDE4D2 monomer,
pIC50 6.0 (IC50 1.018x10-6 M) [2]
Description: Inhibition of a fluorescent determination of reaction rate of cAMP hydrolysis by purified human PDE4D7-S129(wt) dimer (basal).
Immunopharmacology Comments
The selective PDE4 inhibitor difamilast (OPA-15406) has been shown to inhibit PDE4D3 [7]. It is a Phase 3 clinical candidate being investigated as a treatment for atopic dermatitis [3].
Immuno Process Associations
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0050852 T cell receptor signaling pathway IMP
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 3 GO processes
GO:0032729 positive regulation of interferon-gamma production IMP
GO:0032743 positive regulation of interleukin-2 production IMP
GO:0032754 positive regulation of interleukin-5 production IMP
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0050852 T cell receptor signaling pathway IMP
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes, IEA only
GO:0050900 leukocyte migration IMP
click arrow to show/hide IEA associations
GO:0030593 neutrophil chemotaxis IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 2 GO processes, IEA only
GO:0050900 leukocyte migration IMP
click arrow to show/hide IEA associations
GO:0030593 neutrophil chemotaxis IEA

References

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1. Albrecht W, Unger A, Bauer SM, Laufer SA. (2017) Discovery of N-{4-[5-(4-Fluorophenyl)-3-methyl-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide (CBS-3595), a Dual p38α MAPK/PDE-4 Inhibitor with Activity against TNFα-Related Diseases. J. Med. Chem., 60 (13): 5290-5305. [PMID:28613871]

2. Gurney ME, Nugent RA, Mo X, Sindac JA, Hagen TJ, Fox 3rd D, O'Donnell JM, Zhang C, Xu Y, Zhang HT et al.. (2019) Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders. J. Med. Chem., 62 (10): 4884-4901. [PMID:31013090]

3. Hanifin JM, Ellis CN, Frieden IJ, Fölster-Holst R, Stein Gold LF, Secci A, Smith AJ, Zhao C, Kornyeyeva E, Eichenfield LF. (2016) OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): A phase-II randomized, double-blind, placebo-controlled study. J. Am. Acad. Dermatol., 75 (2): 297-305. [PMID:27189825]

4. Houslay MD, Adams DR. (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem. J., 370 (Pt 1): 1-18. [PMID:12444918]

5. Huang Z, Dias R, Jones T, Liu S, Styhler A, Claveau D, Otu F, Ng K, Laliberte F, Zhang L et al.. (2007) L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition. Biochem. Pharmacol., 73 (12): 1971-81. [PMID:17428447]

6. Moslin R, Gardner D, Santella J, Zhang Y, Duncia JV, Liu C, Lin J, Tokarski JS, Strnad J, Pedicord D et al.. (2017) Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling. Medchemcomm, 8 (4): 700-712. DOI: 10.1039/C6MD00560H [PMID:30108788]

7. Okada M, Kato M, Sato N, Uno T, Kitagaki H, Haruta J, Hiyama H, Shibata T. (2007) Oxazole compound and pharmaceutical composition. Patent number: WO2007058338. Assignee: Otsuka Pharmaceutical Co., Ltd.. Priority date: 24/05/2007. Publication date: 15/11/2005.

8. Perry MJ, O'Connell J, Walker C, Crabbe T, Baldock D, Russell A, Lumb S, Huang Z, Howat D, Allen R et al.. (1998) CDP840: a novel inhibitor of PDE-4. Cell Biochem Biophys., 29: 113-32. [PMID:9631241]

9. Saldou N, Obernolte R, Huber A, Baecker PA, Wilhelm R, Alvarez R, Li B, Xia L, Callan O, Su C et al.. (1998) Comparison of recombinant human PDE4 isoforms: interaction with substrate and inhibitors. Cell. Signal., 10 (6): 427-40. [PMID:9720765]

10. Schafer PH, Parton A, Capone L, Cedzik D, Brady H, Evans JF, Man HW, Muller GW, Stirling DI, Chopra R. (2014) Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell. Signal., 26 (9): 2016-29. [PMID:24882690]

11. Tsai YF, Chu TC, Chang WY, Wu YC, Chang FR, Yang SC, Wu TY, Hsu YM, Chen CY, Chang SH et al.. (2017) 6-Hydroxy-5,7-dimethoxy-flavone suppresses the neutrophil respiratory burst via selective PDE4 inhibition to ameliorate acute lung injury. Free Radic. Biol. Med., 106: 379-392. [PMID:28263828]

12. Wang P, Myers JG, Wu P, Cheewatrakoolpong B, Egan RW, Billah MM. (1997) Expression, purification, and characterization of human cAMP-specific phosphodiesterase (PDE4) subtypes A, B, C, and D. Biochem. Biophys. Res. Commun., 234 (2): 320-4. [PMID:9177268]

13. Zhang X, Dong G, Li H, Chen W, Li J, Feng C, Gu Z, Zhu F, Zhang R, Li M et al.. (2019) Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent. J. Med. Chem., 62 (11): 5579-5593. [PMID:31099559]

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