PDE4D

Summary

PDE4D (phosphodiesterase 4D, HGNC:8783) is a protein-coding gene on chromosome 5q11.2-q12.1, encoding 3’,5’-cyclic-AMP phosphodiesterase 4D (Q08499). Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

This gene encodes one of four mammalian counterparts to the fruit fly ‘dunce’ gene. The encoded protein has 3’,5’-cyclic-AMP phosphodiesterase activity and degrades cAMP, which acts as a signal transduction molecule in multiple cell types. This gene uses different promoters to generate multiple alternatively spliced transcript variants that encode functional proteins.

Source: NCBI Gene 5144 — RefSeq curated summary.

At a glance

• Gene–disease (curated): acrodysostosis 2 with or without hormone resistance (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 31
• Clinical variants (ClinVar): 673 total — 13 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 110
• Druggable target: yes — 269 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001104631

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8783
Approved symbol	PDE4D
Name	phosphodiesterase 4D
Location	5q11.2-q12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000113448
Ensembl biotype	protein_coding
OMIM	600129
Entrez	5144

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 14 protein_coding, 6 retained_intron, 5 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000309641, ENST00000317118, ENST00000340635, ENST00000358923, ENST00000360047, ENST00000405053, ENST00000405755, ENST00000502484, ENST00000502575, ENST00000503258, ENST00000504624, ENST00000505453, ENST00000505507, ENST00000506024, ENST00000506510, ENST00000507116, ENST00000509355, ENST00000509368, ENST00000511382, ENST00000512069, ENST00000514231, ENST00000514552, ENST00000515011, ENST00000515324, ENST00000515835, ENST00000621323, ENST00000636120

RefSeq mRNA: 17 — MANE Select: NM_001104631 NM_001104631, NM_001165899, NM_001197218, NM_001197219, NM_001197220, NM_001197221, NM_001197222, NM_001197223, NM_001349241, NM_001349242, NM_001349243, NM_001364599, NM_001364600, NM_001364602, NM_001364603, NM_001364604, NM_006203

CCDS: CCDS47213, CCDS54858, CCDS54859, CCDS56369, CCDS56370, CCDS56371, CCDS56372, CCDS56373, CCDS87297, CCDS93714

Canonical transcript exons

ENST00000340635 — 15 exons

Exon	Start	End
ENSE00001559328	59893168	59893726
ENSE00002067850	58969038	58975080
ENSE00003461387	59215777	59215968
ENSE00003518137	58989755	58989919
ENSE00003521505	59180595	59180644
ENSE00003534733	58977191	58977345
ENSE00003548061	58993372	58993465
ENSE00003572379	58976350	58976472
ENSE00003585964	58990804	58990902
ENSE00003613970	58988493	58988592
ENSE00003623653	59193500	59193536
ENSE00003633267	58991832	58992004
ENSE00003652328	58975657	58975839
ENSE00003655054	59185189	59185262
ENSE00003674506	59038859	59038971

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 96.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.3955 / max 873.9007, expressed in 1555 samples.

FANTOM5 promoters (68 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61850	3.1558	274
61860	2.2054	659
61811	1.8956	625
61863	1.7743	576
61807	1.6731	496
61805	1.5078	438
61841	1.1149	180
61803	1.0865	289
61886	0.9824	145
61849	0.7689	156

Top tissues by expression

297 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gluteal muscle	UBERON:0002000	96.98	gold quality
biceps brachii	UBERON:0001507	96.23	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.19	gold quality
triceps brachii	UBERON:0001509	96.08	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.83	gold quality
diaphragm	UBERON:0001103	95.75	gold quality
calcaneal tendon	UBERON:0003701	95.27	gold quality
skeletal muscle tissue	UBERON:0001134	95.14	gold quality
gastrocnemius	UBERON:0001388	95.04	gold quality
vastus lateralis	UBERON:0001379	94.73	gold quality
muscle organ	UBERON:0001630	94.53	gold quality
skeletal muscle organ	UBERON:0014892	94.53	gold quality
quadriceps femoris	UBERON:0001377	94.40	gold quality
muscle of leg	UBERON:0001383	94.37	gold quality
buccal mucosa cell	CL:0002336	93.95	gold quality
deltoid	UBERON:0001476	93.83	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.39	gold quality
heart right ventricle	UBERON:0002080	93.31	gold quality
cauda epididymis	UBERON:0004360	93.31	gold quality
muscle tissue	UBERON:0002385	93.30	gold quality
saphenous vein	UBERON:0007318	92.46	gold quality
tendon	UBERON:0000043	92.00	gold quality
colonic epithelium	UBERON:0000397	91.92	gold quality
tibialis anterior	UBERON:0001385	91.65	silver quality
lower lobe of lung	UBERON:0008949	91.21	gold quality
popliteal artery	UBERON:0002250	90.59	gold quality
tibial artery	UBERON:0007610	90.59	gold quality
cortical plate	UBERON:0005343	90.52	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.30	gold quality
seminal vesicle	UBERON:0000998	89.90	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	18800.15
E-GEOD-131882	yes	18029.28
E-ANND-2	yes	11745.06
E-HCAD-35	yes	100.48
E-HCAD-25	yes	92.42
E-ANND-3	yes	22.46
E-CURD-46	yes	16.65
E-MTAB-6678	yes	5.17
E-HCAD-30	no	2998.99
E-CURD-112	no	2.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1

miRNA regulators (miRDB)

397 targeting PDE4D, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia (PMID:11839681)
• PDE4D5 is upregulated in tracheal smooth muscle cells because of a CRE-containing, isoform-specific promoter (PMID:12121997)
• Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins show a role for PDE4D (PMID:12399592)
• Reported here the cloning and characterization of two novel PDE4D isoforms, PDE4D6 and PDE4D7. (PMID:12834813)
• fine mapping of locus and testing for association with stroke (PMID:14517540)
• In the crystal structure of PDE4D2 catalytic domain in complex with AMP, two divalent metal ions simultaneously interact with the phosphate group of AMP, implying a binuclear catalysis. (PMID:14609333)
• Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine (PMID:14668322)
• oligomerization state determines regulatory properties and inhibitor sensitivity of PDE4 (PMID:15131123)
• PDE4D forms a cAMP diffusion barrier at the apical membrane of the airway epithelium (PMID:15611099)
• Variants in the ALOX5AP gene but not the PDE4D gene are associated with risk for stroke in individuals from central Europe (PMID:15731479)
• Lack of association of the PDE4D gene as a major risk factor for ischemic stroke, or early carotid atherosclerosis. (PMID:15802632)
• Studies that employ genome-wide linkage scans with hundreds of small nuclear families have identified new susceptibility genes for coronary artery disease and myocardiaI infarction, including PDE4D (encoding phosphodiesterase 4D) for ischemic stroke. (PMID:15861005)
• genetic analysis of linkage of stroke susceptibility to the PDE4D gene region on chromosome 5q (PMID:16020760)
• The data of this study suggest that common variants in PDE4D may contribute to the genetic risk for ischemic stroke in multiple populations. (PMID:16130105)
• There was familial aggregation of ischemic stroke and a difference in degree of familial clustering between stroke subtypes. The authors also found that the PDE4D gene is significantly associated with small-vessel infarction in inbred individuals. (PMID:16162858)
• the PDE4D polymorphism may have a role in development of ischemic stroke in Pakistan (PMID:16166573)
• STRK1 may have a role in development of cerebral infarction (PMID:16322495)
• PDE4D may have a role in ischemic stroke and cardioembolic stroke (PMID:16373644)
• Results suggest that gravin maintains a signaling complex that includes protein kinase A and phosphodiesterase 4D. (PMID:16642035)
• Four of the SNPs and the microsatellite AC008818-1 showed association with stroke after stratification by hypertension. (PMID:16675738)
• RACK1 and beta-arrestin compete to sequester distinct ‘pools’ of PDE4D5. (PMID:16689683)
• Modest associations between several PDE4D gene polymorphisms and risk of incident ischemic stroke in men without baseline hypertension. (PMID:16825591)
• results and the pooled analyses from all the studies indicate a strong association between PDE4D and ischaemic stroke; this strengthens the evidence that PDE4D plays a key part in the pathogenesis of ischaemic stroke (PMID:16914755)
• We identify a novel process through which reactive oxygen species activate long PDE4 isoforms so as to reduce cAMP levels and thereby promote inflammatory responses. (PMID:16973330)
• SNP13 and haplotypes, SNP7 G/A and IL13 +2044 G/A, may be useful for predicting chronic obstructive pulmonary disease susceptibility. (PMID:17016624)
• cAMP-PDE activity is upregulated in malignant cells of human salivary glands (PMID:17065074)
• Compartmentalized PDE4B acts as a sink to drain cAMP from discrete locations, resulting in multiple domains with different cAMP concentrations. (PMID:17088426)
• Significantly different distributions were seen with respect to the AC008818-1 alleles. Allele 148 associates with an increased risk of stroke incidence, & allele 144 with a protective effect. PDE4D may be involved in stroke etiology and pathogenesis. (PMID:17594329)
• The PDE4D SNPs, showed a non-significant risk in the ICVD group which increased for the Large Artery Atherosclerosis subtype. (PMID:17655870)
• that PDE4D5, despite being a minor component of the tissue PDE pool, is the key physiological regulator of beta(2)AR-induced cAMP turnover within human airway smooth muscle. (PMID:17673687)
• Cells can contain several non-overlapping PKA- and EPAC-based signaling complexes that allow PDE4D/PDE3B coordination of cell adhesion. (PMID:17884339)
• Examined interactions between phosphodiesterase 4D5 (PDE4D5) and beta-arrestin and RACK1. (PMID:17900862)
• beta-arrestin-sequestered PDE4D5 shapes the spatial cAMP gradient around the membrane-bound beta(2)-AR, regulating its phosphorylation by protein kinase A (PMID:17956250)
• Meta-analysis of ischemic stroke patients and controls indicates that T alleles of preselected single nucleotide polymorphisms SNP45 and SNP39 in the PDE4D genome region are ischemic stroke risk reducers, especially among subjects with hypertension. (PMID:18398440)
• No genetic variant examined in PDE4D showed a robust and reproducible association to ischemic stroke [meta-analysis] (PMID:18420948)
• There may be racial differences in the prevalence of mutations but still many questions remain unsolved regarding the role of PDE4D in stroke development. [REVIEW] (PMID:18705898)
• Some polymorphisms of PDE4D show associations with personality traits related to neuroticism. (PMID:18711446)
• findings show that polymorphisms in the PDE4D gene are associated with an increased risk of ischaemic stroke in the Chinese Han population. (PMID:19196240)
• variations in PDE4D are not associated with ischemic stroke risk in the Japanese population (PMID:19246712)
• A Cyclic Nucleotide Phosphodiesterases, Type 4 single nucleotide polymorphism as a candidate marker for susceptibility to ischemic stroke. (PMID:19399275)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pde4d	ENSDARG00000032761
mus_musculus	Pde4d	ENSMUSG00000021699
rattus_norvegicus	Pde4d	ENSRNOG00000042536
drosophila_melanogaster	Pde11	FBGN0085370
drosophila_melanogaster	Pde8	FBGN0266377
caenorhabditis_elegans		WBGENE00008443
caenorhabditis_elegans	pde-6	WBGENE00022389

Paralogs (20): PDE4A (ENSG00000065989), PDE8A (ENSG00000073417), PDE6C (ENSG00000095464), PDE4C (ENSG00000105650), PDE10A (ENSG00000112541), PDE8B (ENSG00000113231), PDE1A (ENSG00000115252), PDE1B (ENSG00000123360), PDE11A (ENSG00000128655), PDE6A (ENSG00000132915), PDE6B (ENSG00000133256), PDE5A (ENSG00000138735), PDE3B (ENSG00000152270), PDE1C (ENSG00000154678), PDE9A (ENSG00000160191), PDE7B (ENSG00000171408), PDE3A (ENSG00000172572), PDE4B (ENSG00000184588), PDE2A (ENSG00000186642), PDE7A (ENSG00000205268)

Protein

Protein identifiers

3’,5’-cyclic-AMP phosphodiesterase 4D — Q08499 (reviewed: Q08499)

Alternative names: DPDE3, PDE43, cAMP-specific phosphodiesterase 4D

All UniProt accessions (8): Q08499, A0A140VJR0, A0A1B0GW84, D6R9L4, D6RAQ0, D6RBB2, D6RHE0, D6RIG1

UniProt curated annotations — full annotation on UniProt →

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

Subunit / interactions. Homodimer for the long isoforms. Isoforms with truncated N-termini are monomeric. Isoform 3 is part of a ternary complex containing PRKAR2A, PRKAR2B and AKAP9. Interacts with PDE4DIP. Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1). Isoform 5, isoform N3 and isoform 12 bind RACK1 via their unique N-terminus. Binds ARRB2. Interacts (via N-terminal region) with SHANK2 (via proline-rich region); the interaction is increased in a PKA-dependent manner.

Subcellular location. Apical cell membrane. Cytoplasm. Membrane. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Expressed in colonic epithelial cells (at protein level). Widespread; most abundant in skeletal muscle. Detected in brain. Detected in brain, placenta, lung and kidney. Detected in heart and skeletal muscle.

Post-translational modifications. Long isoforms that share a conserved PKA phosphorylation site in the N-terminus are activated by PKA through phosphorylation. Isoform 3 and isoform 7 are activated by phosphorylation (in vitro), but not isoform 6. Isoform N3 and isoform 12 are phosphorylated on Ser-49, Ser-51, Ser-55 and Ser-59. Sumoylation of long isoforms by PIAS4 augments their activation by PKA phosphorylation and represses their inhibition by ERK phosphorylation.

Disease relevance. Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. Acrodysostosis 2, with or without hormone resistance (ACRDYS2) [MIM:614613] A pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by rolipram. Activated by phosphatidic acid.

Cofactor. Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions. Binds 2 divalent metal cations per subunit. Site 2 has a preference for magnesium and/or manganese ions.

Pathway. Purine metabolism; 3’,5’-cyclic AMP degradation; AMP from 3’,5’-cyclic AMP: step 1/1.

Miscellaneous. Activated by phosphorylation at Ser-53. Mutagenesis of Ser-54 abolishes activation.

Similarity. Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily.

Isoforms (12)

UniProt ID	Names	Canonical?
Q08499-1	4, hPDE4D4	yes
Q08499-2	3, hPDE4D3
Q08499-3	10
Q08499-4	1, hPDE4D1
Q08499-5	2, hPDE4D2
Q08499-6	5, hPDE4D5
Q08499-7	N3, PDE4DN3
Q08499-8	6, PDE4D6
Q08499-9	8, PDE4D8
Q08499-10	9, PDE4D9
Q08499-11	7, PDE4D7
Q08499-12	12

RefSeq proteins (17): NP_001098101, NP_001159371, NP_001184147, NP_001184148, NP_001184149, NP_001184150, NP_001184151, NP_001184152, NP_001336170, NP_001336171, NP_001336172, NP_001351528, NP_001351529, NP_001351531, NP_001351532, NP_001351533, NP_006194 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002073	PDEase_catalytic_dom	Domain
IPR023088	PDEase	Family
IPR023174	PDEase_CS	Conserved_site
IPR036971	PDEase_catalytic_dom_sf	Homologous_superfamily
IPR040844	PDE4_UCR	Domain

Pfam: PF00233, PF18100

Enzyme classification (BRENDA):

• EC 3.1.4.53 — 3’,5’-cyclic-AMP phosphodiesterase (BRENDA: 28 organisms, 62 substrates, 307 inhibitors, 60 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ADENOSINE 3’,5’-CYCLIC PHOSPHATE	—	34
3’,5’-CAMP	0.0003–0.5	13
CAMP	0.0001–0.191	9
CGMP	0.24–0.427	2
3’,5’-CGMP	1.6	1
GUANOSINE 3’,5’-CYCLIC PHOSPHATE	0.124	1

Catalyzed reactions (Rhea), 1 shown:

• 3’,5’-cyclic AMP + H2O = AMP + H(+) (RHEA:25277)

UniProt features (117 total): helix 27, splice variant 17, binding site 16, modified residue 12, sequence variant 12, turn 9, strand 5, region of interest 4, compositionally biased region 4, sequence conflict 4, mutagenesis site 3, chain 1, domain 1, active site 1, cross-link 1

Structure

Experimental structures (PDB)

122 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1Y2K	X-RAY DIFFRACTION	1.36
8W4R	X-RAY DIFFRACTION	1.37
1Y2B	X-RAY DIFFRACTION	1.4
6FDC	X-RAY DIFFRACTION	1.45
6LRM	X-RAY DIFFRACTION	1.45
6IMI	X-RAY DIFFRACTION	1.46
6IMT	X-RAY DIFFRACTION	1.48
6IMD	X-RAY DIFFRACTION	1.5
7B9H	X-RAY DIFFRACTION	1.5
7CBJ	X-RAY DIFFRACTION	1.5
6IMR	X-RAY DIFFRACTION	1.5
1XOR	X-RAY DIFFRACTION	1.54
7YQF	X-RAY DIFFRACTION	1.54
6IMB	X-RAY DIFFRACTION	1.55
1XOM	X-RAY DIFFRACTION	1.55
6IMO	X-RAY DIFFRACTION	1.55
8W4Q	X-RAY DIFFRACTION	1.55
8WDN	X-RAY DIFFRACTION	1.55
2PW3	X-RAY DIFFRACTION	1.56
2QYN	X-RAY DIFFRACTION	1.57
7CBQ	X-RAY DIFFRACTION	1.59
1TBB	X-RAY DIFFRACTION	1.6
5WH6	X-RAY DIFFRACTION	1.6
6ZBA	X-RAY DIFFRACTION	1.6
6F8W	X-RAY DIFFRACTION	1.6
1TB7	X-RAY DIFFRACTION	1.63
7YSX	X-RAY DIFFRACTION	1.65
7AY6	X-RAY DIFFRACTION	1.66
1Y2C	X-RAY DIFFRACTION	1.67
8WDO	X-RAY DIFFRACTION	1.67

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08499-F1	68.01	0.40

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 462 (proton donor)

Ligand- & substrate-binding residues (16): 462; 462; 466; 502; 503; 503; 503; 503; 503; 620; 620; 623 …

Post-translational modifications (13): 54, 59, 63, 59, 63, 59, 63, 142, 299, 301, 348, 375, 387

Mutagenesis-validated functional residues (3):

Position	Phenotype
503	decreased 3’,5’-cyclic-amp phosphodiesterase activity. loss of mg2(+)-binding.
527	abolishes homodimerization.
563	abolishes homodimerization.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-180024	DARPP-32 events
R-HSA-418555	G alpha (s) signalling events
R-HSA-9860927	Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells

MSigDB gene sets: 859 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, LEE_SP4_THYMOCYTE, BROWNE_HCMV_INFECTION_4HR_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, GGTGTGT_MIR329, WWTAAGGC_UNKNOWN, HNF3ALPHA_Q6, PAX4_01, TGCGCANK_UNKNOWN, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_255, GOBP_EPITHELIAL_CELL_DEVELOPMENT, TTTGTAG_MIR520D

GO Biological Process (20): regulation of heart rate (GO:0002027), cAMP catabolic process (GO:0006198), positive regulation of heart rate (GO:0010460), regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0010880), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-2 production (GO:0032743), positive regulation of interleukin-5 production (GO:0032754), negative regulation of heart contraction (GO:0045822), T cell receptor signaling pathway (GO:0050852), establishment of endothelial barrier (GO:0061028), cellular response to cAMP (GO:0071320), cellular response to epinephrine stimulus (GO:0071872), adrenergic receptor signaling pathway (GO:0071875), regulation of cardiac muscle cell contraction (GO:0086004), negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106072), negative regulation of cAMP/PKA signal transduction (GO:0141162), regulation of cell communication by electrical coupling involved in cardiac conduction (GO:1901844), negative regulation of relaxation of cardiac muscle (GO:1901898), regulation of calcium ion transmembrane transport via high voltage-gated calcium channel (GO:1902514), signal transduction (GO:0007165)

GO Molecular Function (16): 3’,5’-cyclic-nucleotide phosphodiesterase activity (GO:0004114), 3’,5’-cyclic-AMP phosphodiesterase activity (GO:0004115), calcium channel regulator activity (GO:0005246), enzyme binding (GO:0019899), signaling receptor regulator activity (GO:0030545), cAMP binding (GO:0030552), beta-2 adrenergic receptor binding (GO:0031698), transmembrane transporter binding (GO:0044325), metal ion binding (GO:0046872), 3’,5’-cyclic-GMP phosphodiesterase activity (GO:0047555), ATPase binding (GO:0051117), scaffold protein binding (GO:0097110), heterocyclic compound binding (GO:1901363), protein binding (GO:0005515), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787)

GO Cellular Component (12): nucleoplasm (GO:0005654), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), voltage-gated calcium channel complex (GO:0005891), cilium (GO:0005929), membrane (GO:0016020), apical plasma membrane (GO:0016324), nuclear membrane (GO:0031965), calcium channel complex (GO:0034704), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Opioid Signalling	1
GPCR downstream signalling	1
Response of endothelial cells to shear stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
positive regulation of cytokine production	3
protein binding	3
regulation of heart contraction	2
3’,5’-cyclic-nucleotide phosphodiesterase activity	2
regulation of biological quality	1
purine ribonucleotide catabolic process	1
cyclic nucleotide catabolic process	1
cAMP metabolic process	1
regulation of heart rate	1
positive regulation of heart contraction	1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of release of sequestered calcium ion into cytosol	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
interleukin-5 production	1
regulation of interleukin-5 production	1
heart contraction	1
negative regulation of blood circulation	1
antigen receptor-mediated signaling pathway	1
endothelial cell development	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
cellular response to chemical stimulus	1
response to epinephrine	1
adrenergic receptor activity	1
G protein-coupled receptor signaling pathway	1
regulation of cardiac muscle contraction	1
cardiac muscle cell contraction	1
regulation of actin filament-based movement	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
negative regulation of G protein-coupled receptor signaling pathway	1
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
cAMP/PKA signal transduction	1
regulation of cAMP/PKA signal transduction	1
negative regulation of intracellular signal transduction	1
regulation of cell communication by electrical coupling	1

Protein interactions and networks

STRING

1404 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE4D	PDE4DIP	Q5VU43	979
PDE4D	AKAP6	Q13023	925
PDE4D	RAPGEF3	O95398	910
PDE4D	ALDH7A1	P49419	910
PDE4D	AKAP1	Q92667	892
PDE4D	AKAP7	O43687	872
PDE4D	ARRB2	P32121	828
PDE4D	AKAP9	Q99996	809
PDE4D	ARRB1	P49407	767
PDE4D	AKAP12	Q02952	764
PDE4D	PRKACA	P17612	751
PDE4D	PRKACG	P22612	750
PDE4D	PRKACB	P22694	750
PDE4D	SLC25A19	Q9HC21	750
PDE4D	ADRB2	P07550	730

IntAct

33 interactions, top by confidence:

A	B	Type	Score
COIL	PDE4D	psi-mi:“MI:0915”(physical association)	0.560
MAGEA6	PDE4D	psi-mi:“MI:0915”(physical association)	0.560
GOLGA8F	PDE4D	psi-mi:“MI:0915”(physical association)	0.560
PDE4D	GOLGA8DP	psi-mi:“MI:0915”(physical association)	0.560
PDE4D	TRAF1	psi-mi:“MI:0915”(physical association)	0.560
PDE4D	COIL	psi-mi:“MI:0915”(physical association)	0.560
PDE4D	GOLGA8F	psi-mi:“MI:0915”(physical association)	0.560
PDE4D	MAGEA6	psi-mi:“MI:0915”(physical association)	0.560
TRAF1	PDE4D	psi-mi:“MI:0915”(physical association)	0.560
ARRB2	PDE4D	psi-mi:“MI:0915”(physical association)	0.560
PDE4D	PDE4B	psi-mi:“MI:0915”(physical association)	0.500
Bub1	NDC80	psi-mi:“MI:0915”(physical association)	0.400
AKAP12	PDE4D	psi-mi:“MI:0915”(physical association)	0.400
SHANK2	PDE4D	psi-mi:“MI:0915”(physical association)	0.400
PDE4D	PCNA	psi-mi:“MI:0915”(physical association)	0.370
PDE4D	CFAP418	psi-mi:“MI:0915”(physical association)	0.370
ECE1	PDE4D	psi-mi:“MI:0915”(physical association)	0.370
ARRB2		psi-mi:“MI:0914”(association)	0.350
rep	VWA8	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350

BioGRID (96): PDE4D (Two-hybrid), TRAF1 (Two-hybrid), COIL (Two-hybrid), GOLGA8EP (Two-hybrid), GOLGA8F (Two-hybrid), PDE4D (Two-hybrid), PDE4D (Affinity Capture-Western), PDE4D (Far Western), PDE4D (Far Western), PDE4D (Two-hybrid), PDE4D (Affinity Capture-MS), PDE4D (Affinity Capture-MS), PDE4D (Affinity Capture-MS), PDE4D (Affinity Capture-MS), PDE4D (Affinity Capture-MS)

ESM2 similar proteins: A2AD83, A4Q9E4, A4Q9F0, A4Q9F1, E1B9D8, F4J394, F4JZ68, F7E540, F8VPZ5, O00443, O43283, P14270, Q08499, Q0P4M4, Q14693, Q1LVQ2, Q5R8X7, Q5R978, Q5RAY1, Q5RBY8, Q5TKR9, Q5U5Z8, Q60592, Q61194, Q64512, Q6DTM3, Q6EEF3, Q6EMB2, Q6IVY4, Q6P5D3, Q6ZN28, Q6ZT98, Q6ZUT3, Q7ZXX2, Q80TF6, Q8BMD7, Q8BPQ7, Q8BRB7, Q8BZ21, Q8CDK2

Diamond homologs: A0A077YBL0, B7YZV4, O18696, O60658, O88502, O89084, O95263, P06776, P12252, P14100, P14270, P14644, P14646, P27815, P30645, P54748, P54750, Q01061, Q01063, Q01064, Q01065, Q01066, Q07343, Q08493, Q08499, Q14123, Q3UEI1, Q61481, Q63421, Q64338, Q64395, Q6NNF2, Q86H13, Q8I5V4, Q8IRU4, Q9I7S6, Q9N2V9, Q9W4S9, Q9W4T4, B3LVW5

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
MAPK1	down-regulates	PDE4D	phosphorylation
Gbeta	down-regulates	PDE4D	phosphorylation
ERK1/2	down-regulates	PDE4D	phosphorylation
PRKACA	up-regulates	PDE4D	phosphorylation
MAPK1	up-regulates	PDE4D	phosphorylation
MAPK3	down-regulates	PDE4D	phosphorylation
PKA	“up-regulates activity”	PDE4D	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

673 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	12
Uncertain significance	291
Likely benign	160
Benign	142

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
101052	NM_001104631.2(PDE4D):c.677T>G (p.Phe226Cys)	Pathogenic
101053	NM_001104631.2(PDE4D):c.2033T>C (p.Ile678Thr)	Pathogenic
1802095	NM_001104631.2(PDE4D):c.956T>C (p.Leu319Pro)	Pathogenic
2203651	NM_001104631.2(PDE4D):c.674C>T (p.Pro225Leu)	Pathogenic
2444421	NM_001104631.2(PDE4D):c.998T>C (p.Ile333Thr)	Pathogenic
30035	NM_001104631.2(PDE4D):c.673C>A (p.Pro225Thr)	Pathogenic
30036	NM_001104631.2(PDE4D):c.677T>C (p.Phe226Ser)	Pathogenic
30037	NM_001104631.2(PDE4D):c.568T>G (p.Ser190Ala)	Pathogenic
30038	NM_001104631.2(PDE4D):c.1759A>C (p.Thr587Pro)	Pathogenic
30039	NM_001104631.2(PDE4D):c.682C>G (p.Gln228Glu)	Pathogenic
30040	NM_001104631.2(PDE4D):c.1952A>C (p.Glu651Ala)	Pathogenic
379784	NM_001104631.2(PDE4D):c.881T>G (p.Leu294Arg)	Pathogenic
40064	NM_001104631.2(PDE4D):c.911C>T (p.Ala304Val)	Pathogenic
1224463	NM_001104631.2(PDE4D):c.1783A>C (p.Thr595Pro)	Likely pathogenic
1514919	NM_001104631.2(PDE4D):c.991_996del (p.Glu331_Phe332del)	Likely pathogenic
30041	NM_001104631.2(PDE4D):c.2018G>A (p.Gly673Asp)	Likely pathogenic
3769802	NM_001104631.2(PDE4D):c.896C>A (p.Ser299Tyr)	Likely pathogenic
452502	NM_001104631.2(PDE4D):c.1010T>G (p.Phe337Cys)	Likely pathogenic
4531995	NM_001104631.2(PDE4D):c.935T>C (p.Leu312Pro)	Likely pathogenic
4687864	NM_001104631.2(PDE4D):c.673C>T (p.Pro225Ser)	Likely pathogenic
4814188	NM_001104631.2(PDE4D):c.947T>A (p.Leu316His)	Likely pathogenic
546176	NM_001104631.2(PDE4D):c.1814A>G (p.Tyr605Cys)	Likely pathogenic
982782	NM_001104631.2(PDE4D):c.569C>T (p.Ser190Phe)	Likely pathogenic
986952	NM_001104631.2(PDE4D):c.575T>C (p.Leu192Pro)	Likely pathogenic
989238	NM_001104631.2(PDE4D):c.2051A>G (p.Glu684Gly)	Likely pathogenic

SpliceAI

5610 predictions. Top by Δscore:

Variant	Effect	Δscore
5:58975076:CCCAC:C	acceptor_gain	1.0000
5:58975077:CCAC:C	acceptor_gain	1.0000
5:58975077:CCACC:C	acceptor_gain	1.0000
5:58975078:CAC:C	acceptor_gain	1.0000
5:58975078:CACC:C	acceptor_gain	1.0000
5:58975081:C:CC	acceptor_gain	1.0000
5:58975081:CT:C	acceptor_loss	1.0000
5:58975082:T:A	acceptor_loss	1.0000
5:58975085:T:C	acceptor_gain	1.0000
5:58975085:T:TC	acceptor_gain	1.0000
5:58975651:CATTA:C	donor_loss	1.0000
5:58975652:ATTAC:A	donor_loss	1.0000
5:58975653:TTACC:T	donor_loss	1.0000
5:58975654:TACCT:T	donor_loss	1.0000
5:58975655:ACCT:A	donor_loss	1.0000
5:58975704:T:C	donor_gain	1.0000
5:58975836:GAAC:G	acceptor_gain	1.0000
5:58975838:AC:A	acceptor_gain	1.0000
5:58975839:CC:C	acceptor_gain	1.0000
5:58975840:C:CA	acceptor_loss	1.0000
5:58975840:C:CC	acceptor_gain	1.0000
5:58976344:CTTTA:C	donor_loss	1.0000
5:58976345:TTTA:T	donor_loss	1.0000
5:58976346:TTA:T	donor_loss	1.0000
5:58976347:TAC:T	donor_loss	1.0000
5:58976348:ACCT:A	donor_loss	1.0000
5:58976349:CC:C	donor_loss	1.0000
5:58976468:AGTAC:A	acceptor_gain	1.0000
5:58976469:GTAC:G	acceptor_gain	1.0000
5:58976470:TAC:T	acceptor_gain	1.0000

AlphaMissense

5371 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:58974980:C:G	R705P	1.000
5:58975028:A:G	L689P	1.000
5:58975038:A:G	W686R	1.000
5:58975038:A:T	W686R	1.000
5:58975047:A:G	W683R	1.000
5:58975047:A:T	W683R	1.000
5:58975699:G:C	S657R	1.000
5:58975699:G:T	S657R	1.000
5:58975701:T:G	S657R	1.000
5:58975734:C:G	G646R	1.000
5:58975734:C:T	G646R	1.000
5:58975770:A:G	W634R	1.000
5:58975770:A:T	W634R	1.000
5:58977283:C:G	G539R	1.000
5:58977288:G:T	A537D	1.000
5:58977291:A:C	L536W	1.000
5:58977296:A:C	H534Q	1.000
5:58977296:A:T	H534Q	1.000
5:58977298:G:C	H534D	1.000
5:58977309:A:T	V530D	1.000
5:58977318:T:A	D527V	1.000
5:58977333:G:T	A522D	1.000
5:58988506:A:C	F513L	1.000
5:58988506:A:T	F513L	1.000
5:58988508:A:G	F513L	1.000
5:58988537:T:A	D503V	1.000
5:58988537:T:G	D503A	1.000
5:58990881:A:G	W404R	1.000
5:58990881:A:T	W404R	1.000
5:58993440:A:G	L316P	1.000

dbSNP variants (sampled 300 via entrez): RS1000000597 (5:59722898 C>T), RS1000002471 (5:60196334 C>A,T), RS1000005324 (5:59421554 C>A), RS1000005862 (5:59634315 C>T), RS1000008207 (5:59906443 A>G), RS1000010372 (5:59428789 C>T), RS1000010983 (5:59541049 G>A), RS1000012254 (5:59346643 C>T), RS1000014904 (5:59469672 A>G), RS1000016887 (5:60432674 A>G), RS1000017977 (5:59861651 T>C), RS1000019087 (5:59294661 A>T), RS1000024696 (5:59818202 T>G), RS1000024921 (5:59638995 T>A), RS1000025364 (5:60119927 C>A)

Disease associations

OMIM: gene MIM:600129 | disease phenotypes: MIM:614613, MIM:123100, MIM:615849, MIM:250215

GenCC curated gene-disease

Disease	Classification	Inheritance
acrodysostosis 2 with or without hormone resistance	Definitive	Autosomal dominant
acrodysostosis with multiple hormone resistance	Supportive	Autosomal dominant
chromosome 5q12 deletion syndrome	Supportive	Unknown
acrodysostosis	Supportive	Autosomal dominant

Mondo (9): acrodysostosis 2 with or without hormone resistance (MONDO:0013822), craniosynostosis (MONDO:0015469), postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (MONDO:0014369), metaphyseal acroscyphodysplasia (MONDO:0009592), esophageal atresia (MONDO:0001044), pyloric stenosis (MONDO:0001561), (MONDO:0017240), chromosome 5q12 deletion syndrome (MONDO:0014298), acrodysostosis (MONDO:0019797)

Orphanet (4): OBSOLETE: Acrodysostosis with multiple hormone resistance (Orphanet:280651), Craniosynostosis (Orphanet:1531), Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (Orphanet:420584), Metaphyseal acroscyphodysplasia (Orphanet:1240)

HPO phenotypes

110 total (30 of 110 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000055	Abnormal female external genitalia morphology
HP:0000135	Hypogonadism
HP:0000194	Open mouth
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000272	Malar flattening
HP:0000280	Coarse facial features
HP:0000283	Broad face
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000505	Visual impairment
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000540	Hypermetropia
HP:0000565	Esotropia

GWAS associations

31 associations (top):

Study	Trait	p-value
GCST000063_1	Neuroticism	2.000000e-06
GCST000081_3	Sleep-related phenotypes	3.000000e-08
GCST000389_1	Asthma	3.000000e-08
GCST001089_8	Esophageal cancer	2.000000e-19
GCST001532_8	Immune response to smallpox vaccine (IL-6)	2.000000e-08
GCST001762_4	Obesity-related traits	2.000000e-06
GCST001773_7	Response to antipsychotic treatment	4.000000e-08
GCST001937_61	Breast cancer	3.000000e-08
GCST002003_3	Adverse response to chemotherapy (neutropenia/leucopenia) (gemcitabine)	3.000000e-06
GCST002568_10	Esophageal squamous cell carcinoma	1.000000e-06
GCST002955_5	Forced expiratory volume in 1 second (occupational environmental exposures interaction)	5.000000e-08
GCST003264_302	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_307	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST003264_671	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_680	Post bronchodilator FEV1/FVC ratio	4.000000e-06
GCST004823_6	Cognitive function	6.000000e-06
GCST004988_196	Breast cancer	4.000000e-09
GCST005316_575	Intelligence (MTAG)	2.000000e-08
GCST006269_1237	General cognitive ability	5.000000e-08
GCST006431_7	Plasma parathyroid hormone levels	2.000000e-06
GCST006936_1	Mitochondrial DNA levels	2.000000e-06
GCST007208_17	Obsessive-compulsive disorder	4.000000e-06
GCST007560_5	Sleep duration (long sleep)	1.000000e-08
GCST007576_32	Chronotype	3.000000e-08
GCST009259_2	Amygdala volume	6.000000e-07
GCST010242_356	HDL cholesterol levels	1.000000e-10
GCST010653_11	Thyroid stimulating hormone levels	1.000000e-09
GCST010701_32	Cortical surface area (MOSTest)	2.000000e-29
GCST010702_115	Subcortical volume (MOSTest)	2.000000e-09
GCST010703_98	Brain morphology (MOSTest)	5.000000e-41

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0004627	IGF-1 measurement
EFO:0004314	forced expiratory volume
EFO:0006994	response to gases and fumes exposure
EFO:0004713	FEV/FVC ratio
EFO:0008354	cognitive function measurement
EFO:0004337	intelligence
EFO:0006312	mitochondrial DNA measurement
EFO:0008328	chronotype measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D004933	Esophageal Atresia	C06.198.330; C06.405.117.260; C16.131.314.330
D017219	Gastric Outlet Obstruction	C06.405.748.340
D011707	Pyloric Stenosis	C06.405.748.340.690
C538179	Acrodysostosis (supp.)
C537350	Metaphyseal acroscyphodysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL2093863 (PROTEIN FAMILY), CHEMBL2095153 (SELECTIVITY GROUP), CHEMBL2111340 (SELECTIVITY GROUP), CHEMBL2363066 (PROTEIN FAMILY), CHEMBL288 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

269 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 505,461 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL12856	INAMRINONE	4	9,690
CHEMBL1355736	THEOPHYLLINE	4	752
CHEMBL1520	VARDENAFIL	4	21,078
CHEMBL189	MILRINONE	4	20,605
CHEMBL191	LOSARTAN	4	88,932
CHEMBL192	SILDENAFIL	4	41,819
CHEMBL193240	ROFLUMILAST	4	19,604
CHEMBL249856	ENOXIMONE	4	5,206
CHEMBL4594287	ENSIFENTRINE	4	499
CHEMBL484785	CRISABOROLE	4	1,482
CHEMBL514800	APREMILAST	4	4,576
CHEMBL628	PENTOXIFYLLINE	4	26,061
CHEMBL779	TADALAFIL	4	23,417
CHEMBL932	DIPYRIDAMOLE	4	51,743
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL1017	TELMISARTAN	4	27,457
CHEMBL1064	SIMVASTATIN	4	123,163
CHEMBL1075	MORICIZINE	4	3,860
CHEMBL1096	AMLEXANOX	4	4,195
CHEMBL1113	AMOXAPINE	4	20,128
CHEMBL1171837	PONATINIB	4
CHEMBL1173055	RUCAPARIB	4
CHEMBL118	CELECOXIB	4
CHEMBL1198857	VILANTEROL	4
CHEMBL1200438	TIOCONAZOLE	4
CHEMBL1200661	UNOPROSTONE ISOPROPYL	4
CHEMBL1200692	OLMESARTAN MEDOXOMIL	4
CHEMBL1200848	HYDROXYPROGESTERONE CAPROATE	4
CHEMBL1200934	NORGESTIMATE	4
CHEMBL1201	THIOTHIXENE	4

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs17382202	Efficacy	3	quetiapine	Schizophrenia
rs17742120	Efficacy	3	quetiapine	Schizophrenia
rs2164660	Efficacy	3	quetiapine	Schizophrenia
rs702553	Efficacy	3	diuretics	Nephrosclerosis

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs702553	PDE4D	3	2.50	1	diuretics
rs17382202	PDE4D	3	0.00	1	quetiapine
rs17742120	MIR582, PDE4D	3	0.00	1	quetiapine
rs2164660	PDE4D	3	0.00	1	quetiapine
rs295943	PDE4D		0.00	0
rs10556657	PDE4D		0.00	0
rs12658429	PDE4D		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Phosphodiesterases, 3’,5’-cyclic nucleotide (PDEs)

Most potent curated ligand interactions (23 total), top 23:

Ligand	Action	Affinity	Parameter
MK-0359	Inhibition	8.92	pIC50
LEO 239652	Inhibition	8.42	pIC50
RS-25344	Inhibition	8.4	pIC50
LEO 29102	Inhibition	8.3	pIC50
CDP840	Inhibition	8.15	pKi
α-mangostin derivative 4e	Inhibition	7.77	pIC50
apremilast	Inhibition	7.48	pIC50
compound 29 [Moslin et al., 2017]	Inhibition	7.37	pIC50
difamilast	Inhibition	7.3	pIC50
rolipram	Inhibition	7.2	pIC50
nerandomilast	Inhibition	7.04	pIC50
toddacoumalone	Inhibition	6.85	pIC50
PDE4 inhibitor 16	Inhibition	6.62	pIC50
mangostanin	Inhibition	6.38	pIC50
Ro20-1724	Inhibition	6.2	pIC50
compound 3m [PMID: 32603117]	Inhibition	6.16	pIC50
CBS-3595	Inhibition	6.1	pIC50
BPN14770	Negative	5.99	pIC50
talaroterphenyl A	Inhibition	5.91	pIC50
α-mangostin	Inhibition	5.88	pIC50
moracin M	Inhibition	5.54	pIC50
6-Hydroxy-5,7-dimethoxyflavone	Inhibition	5.45	pIC50
arctigenin	Inhibition	5.42	pIC50

Binding affinities (BindingDB)

363 measured of 620 human assays (626 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-(dibenzofuran-2-ylmethyl)-1-ethyl-6,7-dimethoxy-2H-isoquinolin-3-one	IC50	0.12 nM	US-9670181: Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
CHEMBL315565	IC50	0.398 nM
3-[(2S)-2-[3-cyclopropoxy-4-(difluoromethoxy)phenyl]-2-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]ethyl]-1-oxidopyridin-1-ium	IC50	0.4 nM
CHEMBL313982	IC50	0.501 nM
3-(4-Chloro-3-fluorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide (7)	IC50	2.35 nM	US-10077269: Imidazopyridazine compounds
3-(4-Chloro-3,5-difluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	5.65 nM	US-9815832: Azabenzimidazole compounds
N-Cyclopropyl-3-(3,4,5-trifluorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxamide,trifluoroacetate salt	IC50	5.77 nM	US-9815832: Azabenzimidazole compounds
tetrahydrobenzothiophene (THBT), 21	IC50	10 nM
N-cyclopropyl-3-[2-(difluoro-methoxy)pyridin-4-yl]imidazo[1,2-b]pyridazine-2-carboxamide	IC50	10.5 nM	US-10077269: Imidazopyridazine compounds
3-(4-chloro-3-fluorophenyl)-N-[(1R,2S)-2-fluorocyclopro-pyl]imidazo[1,2-b]pyridazine-2-carboxamide	IC50	11.7 nM	US-10077269: Imidazopyridazine compounds
N-Cyclopropyl-3-(3,4-dichlorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	12.2 nM	US-9815832: Azabenzimidazole compounds
1-ethyl-6,7-dimethoxy-4-[(7-methoxyquinolin-3-yl)methyl]-2H-isoquinolin-3-one	IC50	13 nM	US-9670181: Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
3-(4-chloro-3-fluorophenyl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide	IC50	13.8 nM	US-10077269: Imidazopyridazine compounds
3-(4-Cyano-3,5-difluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	13.8 nM	US-9815832: Azabenzimidazole compounds
Azetidin-1-yl[3-(4-chloro-3,5-difluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]methanone	IC50	14.2 nM	US-9815832: Azabenzimidazole compounds
Azetidin-1-yl[3-(4-chloro-3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]methanone	IC50	15.2 nM	US-9815832: Azabenzimidazole compounds
3-(3-Chloro-4-fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	15.7 nM	US-9815832: Azabenzimidazole compounds
3-(3-Chloro-4-methylphenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	15.9 nM	US-9815832: Azabenzimidazole compounds
4-[2-(Azetidin-1-ylcarbonyl)-3H-imidazo[4,5-b]pyridin-3-yl]-2-fluorobenzonitrile	IC50	16 nM	US-9815832: Azabenzimidazole compounds
N-cyclopropyl-3-(3-fluoro-4-methylphenyl)imidazo[1,2-b]pyridazine-2-carboxamide	IC50	16.8 nM	US-10077269: Imidazopyridazine compounds
4-[3-(3-chlorophenyl)-7-methoxy-2,4-dioxo-4aH-pyrimido[5,4-c]quinolin-1-ium-1-yl]cyclohexane-1-carboxylic acid	IC50	17 nM	US-9833457: Tricyclic compounds as modulators of TNF-α synthesis and as PDE4 inhibitors
azetidin-1-yl-[3-(4-chloro-3-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone	IC50	17.3 nM	US-10077269: Imidazopyridazine compounds
3-(4-Chloro-3-fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	18.4 nM	US-9815832: Azabenzimidazole compounds
azetidin-1-yl-[3-(3-chloro-4-methylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone	IC50	19 nM	US-10077269: Imidazopyridazine compounds
3-(4-chloro-5-fluoro-2-methylphenyl)-N-propan-2-ylimidazo[1,2-b]pyridazine-2-carboxamide	IC50	20 nM	US-10077269: Imidazopyridazine compounds
bis(ditert-butyl-[4-(dimethylamino)phenyl]phosphanium);dichloropalladium	IC50	20 nM	US-9598421: Imidazopyridazine compounds
3-(3-chlorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide	IC50	21 nM	US-10077269: Imidazopyridazine compounds
azetidin-1-yl-[3-[2-(difluoromethoxy)-4-pyridinyl]imidazo[1,2-b]pyridazin-2-yl]methanone	IC50	22.2 nM	US-10077269: Imidazopyridazine compounds
azetidin-1-yl-[3-(4-chloro-3,5-difluorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone	IC50	23.9 nM	US-10077269: Imidazopyridazine compounds
3-(4-chlorophenyl)-N-(2-methylcyclopropyl)imidazo[1,2-b]pyridazine-2-carboxamide	IC50	24.5 nM	US-10077269: Imidazopyridazine compounds
tetrahydrobenzothiophene (THBT), 22	IC50	25 nM
3-(4-chloro-2-fluorophenyl)-N-[(1R,2S)-2-fluorocyclopro-pyl]imidazo[1,2-b]pyridazine-2-carboxamide	IC50	25.1 nM	US-10077269: Imidazopyridazine compounds
3-(4-cyano-3-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide	IC50	25.5 nM	US-10077269: Imidazopyridazine compounds
3-(4-chloro-3-fluorophenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide	IC50	25.8 nM	US-10077269: Imidazopyridazine compounds
3-(4-Chlorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide (2)	IC50	27.9 nM	US-10077269: Imidazopyridazine compounds
3-(4-chloro-2,5-difluorophenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide	IC50	29.2 nM	US-10077269: Imidazopyridazine compounds
N-Cyclopropyl-3-(3-fluoro-4-methylphenyl)-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	31.8 nM	US-9815832: Azabenzimidazole compounds
ethyl 3,5-dimethyl-1-(3-nitrophenyl)-1H-pyrazole-4-carboxylate	IC50	33 nM
N-Cyclopropyl-3-(3,4-difluorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	34.9 nM	US-9815832: Azabenzimidazole compounds
3-(4-Chloro-3-fluorophenyl)-N-propyl-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	38.1 nM	US-9815832: Azabenzimidazole compounds
3-(4-chlorophenyl)-N-[(1R,2S)-2-fluorocyclopro-pyl]imidazo[1,2-b]pyridazine-2-carboxamide	IC50	39.3 nM	US-10077269: Imidazopyridazine compounds
azetidin-1-yl-[3-(3,4-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone	IC50	40 nM	US-10077269: Imidazopyridazine compounds
3-(4-Cyano-3-fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	40.8 nM	US-9815832: Azabenzimidazole compounds
N-Cyclopropyl-3-[3-(methylsulfanyl)phenyl]-3H-imidazo[4,5-b]pyridine-2-carboxamide	IC50	40.9 nM	US-9815832: Azabenzimidazole compounds
3-(4-cyano-2,5-difluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide	IC50	42.5 nM	US-10077269: Imidazopyridazine compounds
[3-(4-chloro-3-fluorophenyl)imidazo[4,5-b]pyridin-2-yl]-(3-fluoroazetidin-1-yl)methanone	IC50	42.6 nM	US-9815832: Azabenzimidazole compounds
3-(4-chloro-3-fluorophenyl)-N-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide	IC50	43.4 nM	US-10077269: Imidazopyridazine compounds
azetidin-1-yl-[3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone	IC50	44.4 nM	US-10077269: Imidazopyridazine compounds
3-(4-chlorophenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide	IC50	47.2 nM	US-10077269: Imidazopyridazine compounds
Azetidin-1-yl[3-(3-fluoro-4-methylphenyl)-3H-imidazo[4,5-b]pyridin-2-yl]methanone	IC50	48.7 nM	US-9815832: Azabenzimidazole compounds

ChEMBL bioactivities

3941 potent at pChembl≥5 of 4699 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	IC50	0.01995	nM	CHEMBL3288029
10.70	IC50	0.01995	nM	CHEMBL3288030
10.70	IC50	0.02	nM	PICLAMILAST
10.68	IC50	0.021	nM	PICLAMILAST
10.59	IC50	0.026	nM	TRANIMILAST
10.52	IC50	0.03	nM	CHEMBL3113966
10.52	IC50	0.03	nM	CHEMBL3113954
10.52	IC50	0.03	nM	CHEMBL3113949
10.52	IC50	0.03	nM	CHEMBL3113948
10.52	IC50	0.03	nM	CHEMBL3968147
10.40	IC50	0.04	nM	CHEMBL3113943
10.40	IC50	0.04	nM	CHEMBL3113976
10.40	IC50	0.04	nM	TRANIMILAST
10.40	IC50	0.04	nM	CHEMBL3113968
10.40	IC50	0.04	nM	CHEMBL3113962
10.30	IC50	0.05	nM	CHEMBL3113964
10.30	IC50	0.05	nM	CHEMBL3113953
10.30	IC50	0.05	nM	CHEMBL3113950
10.30	IC50	0.05	nM	CHEMBL3113946
10.30	IC50	0.05	nM	CHEMBL3113943
10.30	IC50	0.05	nM	CHEMBL4800045
10.29	IC50	0.051	nM	CHEMBL65426
10.22	IC50	0.06	nM	CHEMBL3113976
10.22	IC50	0.06	nM	TRANIMILAST
10.22	IC50	0.06	nM	CHEMBL3113967
10.22	IC50	0.06	nM	CHEMBL3113955
10.22	IC50	0.06	nM	CHEMBL3113951
10.21	Ki	0.06166	nM	CHEMBL4566742
10.15	IC50	0.07	nM	CHEMBL3113978
10.15	IC50	0.07	nM	CHEMBL371037
10.14	IC50	0.072	nM	CHEMBL3113937
10.10	IC50	0.08	nM	CHEMBL67668
10.10	IC50	0.08	nM	CHEMBL3113963
10.10	IC50	0.08	nM	CHEMBL3113947
10.10	IC50	0.08	nM	CHEMBL3113945
10.05	IC50	0.09	nM	CHEMBL3113958
10.05	IC50	0.09	nM	CHEMBL199015
10.00	IC50	0.1	nM	CHEMBL3113939
10.00	IC50	0.1	nM	CHEMBL377709
10.00	IC50	0.1	nM	CHEMBL380321
10.00	IC50	0.1	nM	CHEMBL382168
10.00	IC50	0.1	nM	CHEMBL206968
10.00	IC50	0.1	nM	CHEMBL5081214
10.00	IC50	0.1	nM	CHEMBL1830646
9.96	IC50	0.11	nM	CHEMBL3113958
9.92	IC50	0.12	nM	CHEMBL3113978
9.92	IC50	0.12	nM	CHEMBL3113975
9.92	IC50	0.12	nM	CHEMBL197392
9.92	IC50	0.12	nM	CHEMBL196969
9.92	Ki	0.1202	nM	CHEMBL4435111

PubChem BioAssay actives

2683 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-cyclopentyloxy-N-(3,5-dichloro-4-pyridinyl)-4-methoxybenzamide	1625378: Inhibition of human His-tagged PDE4D catalytic domain expressed in Escherichia coli BL21-CodonPlus(DE3) cells using [3H]cAMP or [3H]cGMP as substrate incubated for 30 mins by scintillation counting method	ic50	<0.0001	uM
3-[3-[5-[(3,5-dichloro-4-pyridinyl)carbamoylamino]-1-ethyl-6-oxopyridazin-3-yl]phenyl]-N-[7-[2-hydroxyethyl(methyl)amino]heptyl]benzamide	1720034: Inhibition of PDE4 (unknown origin) expressed in Saccharomyces cerevisiae using [3H] cAMP as substrate incubated for 1 hr by scintillation proximity assay	ic50	<0.0001	uM
(E)-3-[3-[6-(2-cyanopropan-2-yl)quinolin-8-yl]phenyl]-2-(4-methylsulfonylphenyl)-N-propan-2-ylprop-2-enamide	257450: Inhibition of LPS-induced TNFalpha production in human whole blood	ic50	0.0001	uM
1-[[3-[6-(2-cyanopropan-2-yl)quinolin-8-yl]phenyl]methyl]-1-(4-methylsulfonylphenyl)-3-propan-2-ylurea	264626: Inhibition of human GST-PDE4D	ic50	0.0001	uM
N-[[3-[6-(2-cyanopropan-2-yl)quinolin-8-yl]phenyl]methyl]-5-methyl-N-(4-methylsulfonylphenyl)-1,2-oxazole-3-carboxamide	264626: Inhibition of human GST-PDE4D	ic50	0.0001	uM
2-[4-cyano-4-[3-cyclopentyloxy-4-(difluoromethoxy)phenyl]piperidin-1-yl]-N-hydroxyacetamide	159794: Inhibition of phosphodiesterase 4 (PDE4) prepared from human U937 cells	ic50	0.0001	uM
1-[[3-[6-(2-cyanopropan-2-yl)quinolin-8-yl]phenyl]methyl]-1-(4-methylsulfonylphenyl)-3-phenylurea	264626: Inhibition of human GST-PDE4D	ic50	0.0001	uM
8-[3-[(E)-2-(5-methyl-2-pyridinyl)-2-(4-methylsulfonylphenyl)ethenyl]phenyl]-6-propan-2-ylquinoline	257450: Inhibition of LPS-induced TNFalpha production in human whole blood	ic50	0.0001	uM
2-[5-[(1S)-1-[3-cyclopropyloxy-4-(difluoromethoxy)phenyl]-2-(1-oxidopyridin-1-ium-3-yl)ethyl]-1,3-thiazol-2-yl]-1,1,1,3,3,3-hexafluoropropan-2-ol	257450: Inhibition of LPS-induced TNFalpha production in human whole blood	ic50	0.0001	uM
5-[5-[(3,5-dichloro-4-pyridinyl)carbamoylamino]-1-ethyl-6-oxopyridazin-3-yl]-3-N-[3-(dimethylamino)propyl]-1-N-ethylbenzene-1,3-dicarboxamide	1720034: Inhibition of PDE4 (unknown origin) expressed in Saccharomyces cerevisiae using [3H] cAMP as substrate incubated for 1 hr by scintillation proximity assay	ic50	0.0001	uM
1-[2-[4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydrophthalazin-2-yl]piperidin-1-yl]-2-oxoethyl]-4,4-dimethylpiperidine-2,6-dione	1605845: Inhibition of human PDE4D2 expressed in Escherichia coli BL21 (DE3) using cAMP as substrate by PDELight HTS cAMP phosphodiesterase Kit based	ki	0.0001	uM
1-[2-[4-[(4aS,8aR)-4-(4-fluorophenyl)-1-oxo-4a,5,8,8a-tetrahydrophthalazin-2-yl]piperidin-1-yl]-2-oxoethyl]-4,4-dimethylpiperidine-2,6-dione	1605845: Inhibition of human PDE4D2 expressed in Escherichia coli BL21 (DE3) using cAMP as substrate by PDELight HTS cAMP phosphodiesterase Kit based	ki	0.0001	uM
1-[3-[[4,4-dimethyl-8-(propan-2-ylamino)-11-oxa-9,14,16-triazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),8,12(17),13,15-hexaen-13-yl]amino]propyl]pyrrolidin-2-one	619274: Inhibition of human PDE4D3 assessed as inhibition of [3H]cAMP hydrolysis to [3H]AMP after 15 mins by scintillation proximity assay	ic50	0.0001	uM
2-[(E)-1-(4-methylsulfonylphenyl)-2-[3-(6-propan-2-ylquinolin-8-yl)phenyl]ethenyl]-1,3-thiazole	257450: Inhibition of LPS-induced TNFalpha production in human whole blood	ic50	0.0001	uM
(E)-2-(4-methylsulfonylphenyl)-N-propan-2-yl-3-[3-(6-propan-2-ylquinolin-8-yl)phenyl]prop-2-enamide	257450: Inhibition of LPS-induced TNFalpha production in human whole blood	ic50	0.0001	uM
1-(4-methylsulfonylphenyl)-1-[[3-[6-(2-methylsulfonylpropan-2-yl)quinolin-8-yl]phenyl]methyl]-3-propan-2-ylurea	264626: Inhibition of human GST-PDE4D	ic50	0.0001	uM
Roflumilast	1703914: Inhibition of human recombinant PDE4D using [3H]cAMP as substrate preincubated with enzyme for 10 mins followed by substrate addition and measured after 15 mins by SPA bead based scintillation counting analysis	ic50	0.0001	uM
(Z)-3-[3-[6-(2-cyanopropan-2-yl)quinolin-8-yl]phenyl]-2-(4-methylsulfonylphenyl)-N-propan-2-ylprop-2-enamide	257450: Inhibition of LPS-induced TNFalpha production in human whole blood	ic50	0.0002	uM
2-[4-cyano-4-(3-cyclobutyloxy-4-methoxyphenyl)piperidin-1-yl]-N-hydroxyacetamide	159794: Inhibition of phosphodiesterase 4 (PDE4) prepared from human U937 cells	ic50	0.0002	uM
3-methyl-5-[(E)-1-(4-methylsulfonylphenyl)-2-[3-(6-propan-2-ylquinolin-8-yl)phenyl]ethenyl]-1,2,4-oxadiazole	257449: Inhibitory activity against PDE4D	ic50	0.0002	uM
8-[3-[2-cyclopropylsulfonyl-2-fluoro-2-(4-methylsulfonylphenyl)ethyl]phenyl]-6-(2-methylsulfonylpropan-2-yl)quinoline	447673: Inhibition of human PDE4	ic50	0.0002	uM
3-methyl-5-[(Z)-1-(4-methylsulfonylphenyl)-2-[3-[6-(2-methylsulfonylpropan-2-yl)quinolin-8-yl]phenyl]ethenyl]-1,2,4-oxadiazole	257450: Inhibition of LPS-induced TNFalpha production in human whole blood	ic50	0.0002	uM
1,1-dicyclopropyl-2-fluoro-2-(4-methylsulfonylphenyl)-3-[3-[6-(2-methylsulfonylpropan-2-yl)quinolin-8-yl]phenyl]propan-1-ol	447673: Inhibition of human PDE4	ic50	0.0002	uM
5-[4-[2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalen-1-yl]-2-pyridinyl]phenanthridin-6-one	159634: In vitro inhibition of Phosphodiesterase 4 from guinea pig lung	ic50	0.0002	uM
(4aS,8aR)-2-[1-(2-aminoquinazolin-4-yl)piperidin-4-yl]-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1-one	1605845: Inhibition of human PDE4D2 expressed in Escherichia coli BL21 (DE3) using cAMP as substrate by PDELight HTS cAMP phosphodiesterase Kit based	ki	0.0002	uM
1-[2-[4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,6,7,8,8a-hexahydrophthalazin-2-yl]piperidin-1-yl]-2-oxoethyl]-4,4-dimethylpiperidine-2,6-dione	1605845: Inhibition of human PDE4D2 expressed in Escherichia coli BL21 (DE3) using cAMP as substrate by PDELight HTS cAMP phosphodiesterase Kit based	ki	0.0002	uM
3-[2-[4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydrophthalazin-2-yl]piperidin-1-yl]-2-oxoethyl]-3-azaspiro[5.5]undecane-2,4-dione	1605845: Inhibition of human PDE4D2 expressed in Escherichia coli BL21 (DE3) using cAMP as substrate by PDELight HTS cAMP phosphodiesterase Kit based	ki	0.0002	uM
1-[2-[4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydrophthalazin-2-yl]piperidin-1-yl]-2-oxoethyl]-3-methylpyrrolidine-2,5-dione	1605845: Inhibition of human PDE4D2 expressed in Escherichia coli BL21 (DE3) using cAMP as substrate by PDELight HTS cAMP phosphodiesterase Kit based	ki	0.0002	uM
(4aS,8aR)-4-(3,4-dimethoxyphenyl)-2-(1-quinazolin-4-ylpiperidin-4-yl)-4a,5,8,8a-tetrahydrophthalazin-1-one	1605845: Inhibition of human PDE4D2 expressed in Escherichia coli BL21 (DE3) using cAMP as substrate by PDELight HTS cAMP phosphodiesterase Kit based	ki	0.0002	uM
[2-(3,5-dichloro-4-pyridinyl)-1-(3,4-dimethoxyphenyl)ethyl] 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate	1720007: Inhibition of PDE4 (unknown origin)	ic50	0.0002	uM
2-[4-[7-ethoxy-2,3-bis(hydroxymethyl)-6-methoxynaphthalen-1-yl]-2-pyridinyl]-4-pyridin-3-ylphthalazin-1-one;hydrochloride	159634: In vitro inhibition of Phosphodiesterase 4 from guinea pig lung	ic50	0.0002	uM
2-[2-[(E)-2-[3-[6-(1-methylsulfonylethyl)quinolin-8-yl]phenyl]-1-(4-methylsulfonylphenyl)ethenyl]-1,3-thiazol-5-yl]propan-2-ol	257450: Inhibition of LPS-induced TNFalpha production in human whole blood	ic50	0.0002	uM
1,3-dibutyl-7-(2-oxopropyl)purine-2,6-dione	155681: Concentration at which 50% of the activity of the Phosphodiesterase 4 from Human U937 cells is inhibited	ic50	0.0002	uM
2-[4-[[8-[3-(difluoromethoxy)phenyl]quinolin-6-yl]methoxy]phenyl]acetic acid	502803: Inhibition of human PDE4D	ic50	0.0002	uM
8-[3-[2-cyclopropylsulfonyl-2-fluoro-2-(4-methylsulfonylphenyl)ethyl]phenyl]-6-(2-methylsulfonylpropan-2-yl)quinoline;hydrochloride	447673: Inhibition of human PDE4	ic50	0.0002	uM
chloromethane;8-[3-[2-cyclopropylsulfonyl-2-fluoro-2-(4-methylsulfonylphenyl)ethyl]phenyl]-6-(2-methylsulfonylpropan-2-yl)quinoline	447673: Inhibition of human PDE4	ic50	0.0002	uM
N-[[3-[6-(2-cyanopropan-2-yl)quinolin-8-yl]phenyl]methyl]-N-(4-methylsulfonylphenyl)benzamide	264626: Inhibition of human GST-PDE4D	ic50	0.0003	uM
propan-2-yl N-[[3-[6-(2-cyanopropan-2-yl)quinolin-8-yl]phenyl]methyl]-N-(4-methylsulfonylphenyl)carbamate	264626: Inhibition of human GST-PDE4D	ic50	0.0003	uM
2-[4-cyano-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]piperidin-1-yl]-N-hydroxyacetamide	159794: Inhibition of phosphodiesterase 4 (PDE4) prepared from human U937 cells	ic50	0.0003	uM
4-[6-[5-(3-cycloheptyl-4-oxo-4a,5,8,8a-tetrahydrophthalazin-1-yl)-2-methoxyphenoxy]hexoxy]benzamide	157302: Inhibition of phosphodiesterase 4 (PDE4) in human neutrophils	ic50	0.0003	uM
2-[4-[3-[6-(2-methylsulfonylpropan-2-yl)quinolin-8-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid	605108: Inhibition of PDE4D	ic50	0.0003	uM
4-[4-[5-(3-cycloheptyl-4-oxo-4a,5,8,8a-tetrahydrophthalazin-1-yl)-2-methoxyphenoxy]butoxy]benzoic acid	157302: Inhibition of phosphodiesterase 4 (PDE4) in human neutrophils	ic50	0.0003	uM
1-[2-[4-[(4aS,8aR)-4-[3,4-bis(difluoromethoxy)phenyl]-1-oxo-4a,5,8,8a-tetrahydrophthalazin-2-yl]piperidin-1-yl]-2-oxoethyl]-4,4-dimethylpiperidine-2,6-dione	1605845: Inhibition of human PDE4D2 expressed in Escherichia coli BL21 (DE3) using cAMP as substrate by PDELight HTS cAMP phosphodiesterase Kit based	ki	0.0003	uM
(4aS,8aR)-2-[1-(4-aminopyrimidin-2-yl)piperidin-4-yl]-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1-one	1605845: Inhibition of human PDE4D2 expressed in Escherichia coli BL21 (DE3) using cAMP as substrate by PDELight HTS cAMP phosphodiesterase Kit based	ki	0.0003	uM
1-[2-[4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydrophthalazin-2-yl]piperidin-1-yl]-2-oxoethyl]-3-benzylpyrrolidine-2,5-dione	1605845: Inhibition of human PDE4D2 expressed in Escherichia coli BL21 (DE3) using cAMP as substrate by PDELight HTS cAMP phosphodiesterase Kit based	ki	0.0003	uM
(4R)-4-[3-cyclopentyloxy-4-(fluoromethoxy)phenyl]pyrrolidin-2-one	1924454: Binding affinity to human PDE4 assessed as dissociation constant	kd	0.0003	uM
2-[4-[3-(hydroxymethyl)-6,7-dimethoxyisoquinolin-1-yl]-2-pyridinyl]-4-(1,3-thiazol-2-yl)phthalazin-1-one;hydrochloride	157744: Inhibition of phosphodiesterase 4	ic50	0.0003	uM
2-[4-[3-(hydroxymethyl)-6,7-dimethoxyisoquinolin-1-yl]-2-pyridinyl]-4-thiophen-2-ylphthalazin-1-one;hydrochloride	157744: Inhibition of phosphodiesterase 4	ic50	0.0003	uM
2,2-dimethyl-3-(4-methylsulfonylphenyl)-4-[3-[6-(2-methylsulfonylpropan-2-yl)quinolin-8-yl]phenyl]butan-1-ol	447673: Inhibition of human PDE4	ic50	0.0003	uM
(4aS,8aR)-4-(3,4-dimethoxyphenyl)-2-[[4-(morpholin-4-ylmethyl)phenyl]methyl]-4a,5,8,8a-tetrahydrophthalazin-1-one;hydrochloride	452084: Inhibition of human recombinant PDE4D catalytic domain cloned from human HL60 cells assessed as inhibition of cAMP hydrolysis	ic50	0.0003	uM

CTD chemical–gene interactions

81 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	affects methylation, decreases expression, affects cotreatment, increases abundance	4
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression, decreases expression	4
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Tobacco Smoke Pollution	decreases expression, increases expression	3
Tretinoin	decreases expression, increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
bisphenol A	affects methylation, affects cotreatment, increases methylation, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	decreases expression, increases abundance, affects methylation, affects cotreatment	2
Colforsin	decreases reaction, increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	increases expression	1
methyleugenol	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression, decreases reaction	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
aflatoxin B2	increases methylation	1
nickel sulfate	increases expression	1
coumarin	increases phosphorylation	1

ChEMBL screening assays

863 unique, capped per target: 805 binding, 33 functional, 23 admet, 2 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000405	Binding	Inhibition of PDE4 in human lung	Recent advances on phosphodiesterase 4 inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. — J Med Chem
CHEMBL4348839	ADMET	Inhibition of PDE4 (unknown origin)	Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability. — J Med Chem
CHEMBL682878	Functional	PDE4-related emetic activity in ferrets after intravenous administration at 10 mg/kg	Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6, 7,1-hi]indoles: discovery of potent, selective phosphodiesterase type 4 inhibitors. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 induced pluripotent stem cell, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A6XP	LCHi002-A	Induced pluripotent stem cell	Male
CVCL_A6XQ	LCHi002-B	Induced pluripotent stem cell	Male
CVCL_C0U5	ACTOne cAMP-PDE4D	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

77 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT00556283	PHASE4	COMPLETED	RCT: STARR vs Biofeedback
NCT00226044	PHASE3	COMPLETED	Rectal and Oral Omeprazole Treatment of Reflux Disease in Infants.
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT03127345	PHASE2	WITHDRAWN	Omega 3 Fatty Acid Treatment for Pediatric Musculoskeletal Health
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type
NCT00769847	Not specified	WITHDRAWN	Endoscopic Treatment for Isolated, Single Suture Craniosynostosis
NCT00773643	Not specified	COMPLETED	Osteogenic Profiling of Tissue From Children With Craniosynostosis
NCT01898650	Not specified	COMPLETED	MRI for Non-invasive Evaluation of Brain Stress
NCT02287805	Not specified	COMPLETED	Qualitative and Quantitative Study Which Aims to Determine the Specifics of the Announcement for the Diagnosis of Patients With Craniosynostosis and Their Parents to Better Support Them in Their Care
NCT02561728	Not specified	WITHDRAWN	Hanger Helmet Study
NCT03025763	Not specified	ACTIVE_NOT_RECRUITING	Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones
NCT03231085	Not specified	COMPLETED	Comparison of the Rate of Preoperative Haemoglobin After Administration of Epoetin Alpha Associated With an Oral Medical Supplementation Versus Intravenous Before Surgery of Craniosynostosis at the Child
NCT04704284	Not specified	COMPLETED	Comparing MRI to CT on Pediatric Craniosynostosis.
NCT05911139	Not specified	ENROLLING_BY_INVITATION	Influence of General Anesthesia on the Dynamic Changes in Brain Damage Markers During and After Craniosynostosis Operations in Infancy
NCT06928727	Not specified	RECRUITING	Ocular Characteristics in Patients With Craniosynostosis
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02466451	Not specified	COMPLETED	Study in Children With the Diagnosis of Congenital Diaphragmatic Hernia (CDH) and Oesophageal Atresia (EA)
NCT02525705	Not specified	COMPLETED	Dumping Syndrome After Operation of Esophageal Atresia Type III
NCT02883725	Not specified	COMPLETED	National Register of Oesophageal Atresia
NCT03023865	Not specified	UNKNOWN	Individualized Management for Long Gap Esophageal Atresia
NCT03415893	Not specified	COMPLETED	High-resolution Esophageal Manometry
NCT03455881	Not specified	UNKNOWN	Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
NCT03615495	Not specified	COMPLETED	Flourish™ Pediatric Esophageal Atresia
NCT03619408	Not specified	UNKNOWN	Management of Esophagitis Following Repair of Esophageal Atresia
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT03730454	Not specified	ACTIVE_NOT_RECRUITING	Transanastomotic Tube for Proximal Esophageal Atresia With Distal Tracheoesophageal Fistula Repair
NCT03767673	Not specified	UNKNOWN	Cardiorespiratory Performance and Pulmonary Microbiome in Patients After Repair of Esophageal Atresia
NCT03999008	Not specified	UNKNOWN	Oral Viscous Budesonide in Anastomotic Stricture After Esophageal Atresia Repair (OVB in EA)
NCT04072419	Not specified	UNKNOWN	Application of Enhanced Recovery After Surgery for Congenital Esophageal Atresia During Perioperative Period
NCT04136795	Not specified	UNKNOWN	Evaluation of the Respiratory Impact After Conventional or Minimally Invasive Esophageal Atresia Surgery
NCT04259528	Not specified	UNKNOWN	Endoscopic Ultrasound Findings in Esophageal Atresia Following Surgical Repair
NCT04522193	Not specified	RECRUITING	Dumping Syndrome and Esophageal Atresia
NCT04901546	Not specified	COMPLETED	Esophageal Atresia: a Natural Experiment of the Effects of Oral Inoculation on the Gut Microbiome
NCT04932746	Not specified	COMPLETED	The Effect of Dexmedetomidine on Oxygen During One Lung Ventilation in Pediatric Surgery.