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phosphodiesterase 4D

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 1303

Nomenclature: phosphodiesterase 4D

Abbreviated Name: PDE4D

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

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 809 5q11.2-q12.1 PDE4D phosphodiesterase 4D
Mouse - 747 13 59.69 cM Pde4d phosphodiesterase 4D, cAMP specific
Rat - 803 2q14 Pde4d phosphodiesterase 4D
Previous and Unofficial Names Click here for help
phosphodiesterase E3 dunce homolog (Drosophila) | cAMP-specific 3',5'-cyclic phosphodiesterase 4D | phosphodiesterase 4D, cAMP specific | phosphodiesterase 4D, cAMP-specific
Database Links Click here for help
Alphafold Q08499 (Hs), Q01063 (Mm), P14270 (Rn)
BRENDA 3.1.4.17
CATH/Gene3D 1.10.1300.10
ChEMBL Target CHEMBL288 (Hs), CHEMBL3846 (Mm), CHEMBL2712 (Rn)
DrugBank Target Q08499 (Hs)
Ensembl Gene ENSG00000113448 (Hs), ENSMUSG00000021699 (Mm), ENSRNOG00000042536 (Rn)
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 Click here for help
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:  3
Enzyme Reaction Click here for help
EC Number: 3.1.4.17
Activator (Human)
PKA-mediated phosphorylation  [6]
Rank order of affinity (Human)
cyclic AMP >> cyclic GMP

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CDP840 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.1 pKi 11
⤷ pKi 8.1 (Ki 7.1x10-9 M) [11]
Description: Inhibition of [3H]-R-rolipram binding to recombinant human PDE4D3 isoenzyme
MK-0359 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.9 pIC50 7
⤷ pIC50 8.9 (IC50 1.2x10-9 M) [7]
LEO 239652 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.4 pIC50 8
⤷ pIC50 8.4 (IC50 3.8x10-9 M) [8]
RS-25344 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.4 pIC50 12
⤷ pIC50 8.4 [12]
LEO 29102 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 2
⤷ pIC50 8.3 (IC50 5x10-9 M) [2]
apremilast Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 13
⤷ pIC50 7.5 (IC50 3.3x10-8 M) [13]
Description: Potency against recombinant human PDE4D2 isoform in a TR-FRET assay.
compound 29 [Moslin et al., 2017] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.4 pIC50 9
⤷ pIC50 7.4 (IC50 4.3x10-8 M) [9]
Description: Binding affinity calculated be measuring displacement of [3H]cAMP binding to purified recombinant His-Tb-hPDE4D2.
difamilast Small molecule or natural product Approved drug Immunopharmacology Ligand Hs Inhibition >7.3 pIC50 10
⤷ pIC50 >7.3 (IC50 <5x10-8 M) [10]
Description: Measuring inhibition of substrate hydrolysis by the PDE4D3 isoform.
rolipram Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 15
⤷ pIC50 7.2 (IC50 6.31x10-8 M) [15]
nerandomilast Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.0 pIC50 5
⤷ pIC50 7.0 (IC50 9.1x10-8 M) [5]
Description: Inhibition of PDE4D2 in vitro.
PDE4 inhibitor 16 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.6 pIC50 17
⤷ pIC50 6.6 (IC50 2.4x10-7 M) [17]
Description: Inhibition of enzymatic activity of the recombinant human PDE4D catalytic domain in vitro.
Ro20-1724 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.2 pIC50 15
⤷ pIC50 6.2 (IC50 6.31x10-7 M) [15]
compound 3m [PMID: 32603117] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.2 pIC50 16
⤷ pIC50 6.2 (IC50 6.99x10-7 M) [16]
Description: Biochemical inhibition of recombinant PDE4D2 catalytic domain (aa86–413).
CBS-3595 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.1 pIC50 1
⤷ pIC50 6.1 (IC50 8x10-7 M) [1]
Description: Determined against the PDE4D3 splice variant.
6-Hydroxy-5,7-dimethoxyflavone Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.4 pIC50 14
⤷ pIC50 5.4 (IC50 3.53x10-6 M) [14]
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 Small molecule or natural product Ligand has a PDB structure Hs Negative 6.0 – 8.1 pIC50 3
⤷ pIC50 8.1 (IC50 7.4x10-9 M) [3]
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) [3]
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) [3]
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) [3]
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 [10]. It is a Phase 3 clinical candidate being investigated as a treatment for atopic dermatitis [4].
Immuno Process Associations
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Immuno Process:  Inflammation
Immuno Process:  Chemotaxis & migration

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. Felding J, Sørensen MD, Poulsen TD, Larsen J, Andersson C, Refer P, Engell K, Ladefoged LG, Thormann T, Vinggaard AM et al.. (2014) Discovery and early clinical development of 2-{6-[2-(3,5-dichloro-4-pyridyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis. J Med Chem, 57 (14): 5893-903. [PMID:24984230]

3. 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]

4. 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]

5. Herrmann FE, Hesslinger C, Wollin L, Nickolaus P. (2022) BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis. Front Pharmacol, 13: 838449. [PMID:35517783]

6. 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]

7. 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]

8. Larsen J, Lambert M, Pettersson H, Vifian T, Larsen M, Ollerstam A, Hegardt P, Eskilsson C, Laursen S, Soehoel A et al.. (2020) Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis. J Med Chem, 63 (23): 14502-14521. [PMID:33054196]

9. 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]

10. 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.

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. Wu Y, Tian YJ, Le ML, Zhang SR, Zhang C, Huang MX, Jiang MY, Zhang B, Luo HB. (2020) Discovery of Novel Selective and Orally Bioavailable Phosphodiesterase-1 Inhibitors for the Efficient Treatment of Idiopathic Pulmonary Fibrosis. J Med Chem, 63 (14): 7867-7879. [PMID:32603117]

17. 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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