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Protein / target

3',5'-cyclic-AMP phosphodiesterase 4D

Encoded byPDE4DQ08499Homo sapiensSwiss-Prot
Clinically validated
Therapeutic maturity
15
Approved medicines
Open Targets target-level
View by indication →
30
Clinical trials
Small-molecule tractable
Druggability
Approved Drug

Protein at a glance

Biological role

3',5'-cyclic-nucleotide phosphodiesterase

Strongest disease association

Acrodysostosis 2 with or without hormone resistance

Via encoding gene PDE4D · Genetic evidence · score 0.94

Therapeutic position

Established drug target

Small molecules

Derived from structured UniProt, Open Targets and literature data on this page.

Protein profile

UniProt 2026_02

Canonical identity and biological annotation from UniProt.

Function overview

Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes

Subcellular location

Apical cell membraneCytoplasmMembraneCytoplasm, cytoskeletonCytoplasm, cytoskeleton, microtubule organizing center, centrosome
Domains and Gene Ontology detail (40)

Domains & features

PDEase

Gene Ontology

  • Capical plasma membrane
  • Ccalcium channel complex
  • Ccentrosome
  • Ccytosol
  • Cmembrane
  • Cplasma membrane
  • Cvoltage-gated calcium channel complex
  • F3',5'-cyclic-AMP phosphodiesterase activity
  • F3',5'-cyclic-GMP phosphodiesterase activity
  • F3',5'-cyclic-nucleotide phosphodiesterase activity
  • FATPase binding
  • Fbeta-2 adrenergic receptor binding

809 aa · 91 kDa · 12 isoforms

Biological roles

Reactome v97

What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.

Ion channel gatingGOImmune signallingGO
View supporting evidence

Ion channel gating

  • ·regulation of calcium ion transmembrane transport via high voltage-gated calcium channel

Immune signalling

  • ·positive regulation of interleukin-2 production
  • ·positive regulation of interleukin-5 production
  • ·T cell receptor signaling pathway
View underlying pathways (3)

Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.

Interaction neighbourhood

STRING v12.0

Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.

PDE4DIPPRKACAAKAP6ARRB2DCKADKPRKACBPRKACGALDH7A1ENPP1PDE4D

10 strongest partners — larger node and heavier line mean higher confidence

Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.

Approved medicines with mapped indications

3 medicines · 6 areas

Approved therapies targeting this protein, grouped by what they are approved to treat — the disease-first view of the medicines below. Relationships come from the canonical approved-indication graph (ChEMBL phase-4), the same source as the drug cards.

Lung Diseases, Obstructive2 medicines
Psoriasis2 medicines
Arthritis, Psoriatic1 medicine
Behcet's Syndrome1 medicine
Immune System Diseases1 medicine
Pulmonary Disease, Chronic Obstructive1 medicine

15 medicines meet Open Targets' target-level approved-medicine definition; the 3 shown here are those on this page with a canonical approved disease indication in the graph. Approved indications from ChEMBL (phase-4), via the canonical drug→disease graph.

Drugs targeting this protein

3

How approved and investigational drugs engage this protein — mechanism and action type, direct vs complex targeting, and how broadly each acts across other targets. A drug-first view (the section above groups the approved ones disease-first); direct binders with few recorded targets are listed first.

amlexanox
ApprovedInhibitor

Phosphodiesterase 4 inhibitor

Indicated for Lung Diseases, Obstructive

Acts on a complex — shared with PDE4A, PDE4B, PDE4C · 1 of 4 recorded protein targets

apremilast
ApprovedInhibitor

Phosphodiesterase 4 inhibitor

Indicated for Arthritis, Psoriatic, Behcet's Syndrome, Immune System Diseases, Psoriasis

Acts on a complex — shared with PDE4A, PDE4B, PDE4C · 1 of 4 recorded protein targets

roflumilast
ApprovedInhibitor

Phosphodiesterase 4 inhibitor

Indicated for Lung Diseases, Obstructive, Psoriasis, Pulmonary Disease, Chronic Obstructive

Acts on a complex — shared with PDE4A, PDE4B, PDE4C · 1 of 4 recorded protein targets

ChEMBL mechanism, action type, target identity and approved indications. Open Targets clinical status.

Translational evidence

Open Targets 26

Why this target matters therapeutically, strongest evidence first. Disease associations are gene-level (via the gene that encodes this protein) and open into the full confidence synthesis; the development universe, tractability and safety annotations are target-level, from Open Targets.

Strongest disease associations · via encoding gene PDE4D

Gene-level evidence surfaced through the gene PDE4Dthat encodes this protein — not a direct protein–disease relationship. Ranked by Forefront's causal-directness weighting, so genetically- and clinically-evidenced diseases lead over ones that merely share the literature.

Acrodysostosis 2 with or without hormone resistance
0.94Well supported

Genetic evidence dominant · Open Targets 0.81

Asthma
0.88Well supported

Clinical evidence dominant · Open Targets 0.68

Pulmonary Disease, Chronic Obstructive
0.75Moderately supported

Clinical evidence dominant · Open Targets 0.61

Dermatitis, Atopic
0.74Moderately supported

Clinical evidence dominant · Open Targets 0.60

Psoriasis
0.74Moderately supported

Clinical evidence dominant · Open Targets 0.60

View evidence synthesis (5)
Acrodysostosis 2 with or without hormone resistanceWell supported
0.94
agreement 0.801.00
Genetic99%Literature1%Genetic literaturedup

Open Targets aggregate 0.81 · 2 independent evidence families · 1 not counted as duplicate

AsthmaWell supported
0.88
agreement 0.770.99
Clinical57%Genetic40%Literature3%

Open Targets aggregate 0.68 · 3 independent evidence families

Pulmonary Disease, Chronic ObstructiveModerately supported
0.75
agreement 0.590.90
Clinical94%Literature6%

Open Targets aggregate 0.61 · 2 independent evidence families

Dermatitis, AtopicModerately supported
0.74
agreement 0.590.90
Clinical96%Literature4%

Open Targets aggregate 0.60 · 2 independent evidence families

PsoriasisModerately supported
0.74
agreement 0.580.89
Clinical94%Literature6%

Open Targets aggregate 0.60 · 2 independent evidence families

The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the per-type scores above show the calculation.

Show all associations
Acrodysostosis 2 with or without hormone resistance0.81
Acrodysostosis0.69
Asthma0.68
Pulmonary Disease, Chronic Obstructive0.61
Dermatitis, Atopic0.60
Psoriasis0.60
Arthritis, Psoriatic0.58

Drug development

29 compounds recorded · 15 approved · 14 in clinical development

Open Targets' development universe — every compound recorded against the target at any stage, not all approved medicines. Distinct from the 3 drugs that target this protein in Forefront's canonical graph (3 with a mapped approved indication, shown above): these count different sets and are not a subset relation.

View all recorded compounds (10)
CILOMILASTPhase 3
OGLEMILASTPhase 2
FLAVOXATEApproval
ROFLUMILASTApproval
OXTRIPHYLLINEApproval
MK-0873Phase 2
LOTAMILASTPhase 2
ENSIFENTRINEApproval
HT-0712Phase 2
IBUDILASTApproval

Open Targets known-drugs universe. Drug name and highest clinical stage only — the disease relationship is NOT read from this slice (it carries trial-context noise); approved indications come from the canonical graph above.

Tractability

Small moleculesStrong

Approved Drug and Structure with Ligand support this modality.

AntibodiesEmerging

Feasibility evidence (uniprot loc high conf and go cc high conf) — no clinical-stage drug of this modality recorded.

Protein degradersEmerging

Feasibility evidence (literature and uniprot ubiquitination) — no clinical-stage drug of this modality recorded.

View underlying tractability evidence (12)
SM · Approved DrugSM · Structure with LigandSM · High-Quality LigandSM · High-Quality PocketSM · Druggable FamilyAB · UniProt loc high confAB · GO CC high confPR · LiteraturePR · UniProt UbiquitinationPR · Database UbiquitinationPR · Half-life DataPR · Small Molecule Binder

Raw Open Targets tractability assessment buckets, by modality.

Safety-related annotations

possible thymus atrophyBowes et al. (2012)antidepressant-like activitiesBowes et al. (2012)vasculitisBowes et al. (2012)anti-inflammatory activitiesBowes et al. (2012)arteritisBowes et al. (2012)emesisBowes et al. (2012)

Terms indexed against this target in Open Targets' safety data, with their datasource. These are annotations, not causal claims: the direction of effect (whether activation or inhibition is implicated), species and evidence strength are not captured here, so an entry does not mean that modulating this target is known to cause that condition.

Clinical trials

30

Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein. Ranked by active status, then clinical phase and recency, and spread across the targeting drugs.

View all trials (26)

RECRUITING · via apremilast · NCT07325266

ACTIVE_NOT_RECRUITING · via apremilast · NCT06324435

ClinicalTrials.gov via the drug-target graph.

What's happening now

12

Recent therapeutic activity around this target — regulatory actions, clinical trials and safety signals for 2 drugs that target this protein, plus publications where such a drug is a genuine subject. Every item is reached indirectly through the drug, not the protein itself; incidental mentions (a paper that merely measures a drug) and press items are excluded.

  1. Indication expanded2026-06-29

    Indication expansion: ROFLUMILAST (NDA215985)

    fda · regulatory · fda · via roflumilast

  2. Indication expanded2025-10-04

    Indication expansion: ROFLUMILAST (NDA215985)

    fda · regulatory · fda · via roflumilast

  3. Indication expanded2024-07-09

    Indication expansion: ROFLUMILAST (NDA215985)

    fda · regulatory · fda · via roflumilast

  4. Regulatory approval2024-04-19

    Approval: Apremilast Accord (EMA)

    ema · regulatory · ema · via apremilast

  5. Indication expanded2023-10-05

    Indication expansion: ROFLUMILAST (NDA215985)

    fda · regulatory · fda · via roflumilast

  6. Regulatory approval2022-07-29

    Approval: ROFLUMILAST (NDA215985)

    fda · regulatory · fda · via roflumilast

  7. New publication2021-06-24
    A multicentre open-label study of apremilast in palmoplantar pustulosis (APLANTUS).

    Journal of the European Academy of Dermatology and Venereology : JEADV · 2021 · 17 citations · Europe PMC · via apremilast

  8. Safety communication2017-01-19

    Drug Safety Update: Apremilast (Otezla ▼): risk of suicidal thoughts and behaviour

    mhra · safety · mhra · via apremilast

  9. Safety communication2014-12-11

    Drug Safety Update: Roflumilast (Daxas▼): risk of suicidal behaviour

    mhra · safety · mhra · via roflumilast

  10. New publication2012-09-14
    Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis.

    Annals of the rheumatic diseases · 2013 · 88 citations · Europe PMC · via apremilast

  11. New publication2009-08-01
    Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials.

    Lancet (London, England) · 2009 · 378 citations · Europe PMC · via roflumilast

  12. New publication2009-08-01
    Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.

    Lancet (London, England) · 2009 · 525 citations · Europe PMC · via roflumilast

Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.