PDE8A

Summary

PDE8A (phosphodiesterase 8A, HGNC:8793) is a protein-coding gene on chromosome 15q25.3, encoding High affinity cAMP-specific and IBMX-insensitive 3’,5’-cyclic phosphodiesterase 8A (O60658). Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE8 subfamily. This PDE hydrolyzes the second messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5151 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 133 total
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002605

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8793
Approved symbol	PDE8A
Name	phosphodiesterase 8A
Location	15q25.3
Locus type	gene with protein product
Status	Approved
Aliases	HsT19550
Ensembl gene	ENSG00000073417
Ensembl biotype	protein_coding
OMIM	602972
Entrez	5151

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 16 protein_coding, 7 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000310298, ENST00000339708, ENST00000394553, ENST00000478717, ENST00000485596, ENST00000557819, ENST00000557954, ENST00000557957, ENST00000558543, ENST00000559086, ENST00000559742, ENST00000560333, ENST00000560789, ENST00000561024, ENST00000561105, ENST00000561374, ENST00000853253, ENST00000853254, ENST00000853255, ENST00000853256, ENST00000853257, ENST00000853258, ENST00000911346, ENST00000962318, ENST00000962319, ENST00000962320, ENST00000962321, ENST00000962322

RefSeq mRNA: 3 — MANE Select: NM_002605 NM_001243137, NM_002605, NM_173454

CCDS: CCDS10336, CCDS10337, CCDS58397

Canonical transcript exons

ENST00000394553 — 22 exons

Exon	Start	End
ENSE00003496254	85100015	85100066
ENSE00003498929	85113873	85114037
ENSE00003511698	85120797	85121014
ENSE00003522851	85076733	85076787
ENSE00003530623	85115439	85115487
ENSE00003544098	85113377	85113447
ENSE00003555402	85115984	85116119
ENSE00003569302	85126207	85126374
ENSE00003584279	85137797	85139142
ENSE00003584756	85091044	85091181
ENSE00003607597	85109053	85109130
ENSE00003633755	85083556	85083644
ENSE00003633900	85100156	85100198
ENSE00003643186	85067014	85067204
ENSE00003647776	85123061	85123193
ENSE00003649736	85097948	85098036
ENSE00003654871	85136534	85136663
ENSE00003665594	85117641	85117839
ENSE00003689793	85075862	85075918
ENSE00003847533	84981856	84982348
ENSE00003893335	85089338	85089416
ENSE00003894685	85064370	85064426

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.8420 / max 108.5483, expressed in 1757 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148167	2.8777	1345
148160	2.4646	1075
148168	1.3020	731
148166	0.7630	394
148161	0.4347	223

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	98.61	gold quality
middle frontal gyrus	UBERON:0002702	98.07	gold quality
adrenal tissue	UBERON:0018303	97.41	gold quality
inferior vagus X ganglion	UBERON:0005363	97.38	gold quality
inferior olivary complex	UBERON:0002127	96.62	gold quality
lateral globus pallidus	UBERON:0002476	96.51	gold quality
subthalamic nucleus	UBERON:0001906	96.47	gold quality
colonic mucosa	UBERON:0000317	95.74	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.62	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.52	gold quality
medulla oblongata	UBERON:0001896	95.45	gold quality
palpebral conjunctiva	UBERON:0001812	95.24	gold quality
cartilage tissue	UBERON:0002418	95.04	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.82	gold quality
dorsal plus ventral thalamus	UBERON:0001897	94.73	gold quality
superior vestibular nucleus	UBERON:0007227	94.67	gold quality
spinal cord	UBERON:0002240	94.66	gold quality
transverse colon	UBERON:0001157	94.18	gold quality
adrenal cortex	UBERON:0001235	94.17	gold quality
right adrenal gland cortex	UBERON:0035827	94.10	gold quality
right adrenal gland	UBERON:0001233	94.06	gold quality
left adrenal gland cortex	UBERON:0035825	94.06	gold quality
substantia nigra pars compacta	UBERON:0001965	94.04	gold quality
rectum	UBERON:0001052	94.01	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.88	gold quality
adrenal gland	UBERON:0002369	93.87	gold quality
ventral tegmental area	UBERON:0002691	93.85	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.75	gold quality
left adrenal gland	UBERON:0001234	93.71	gold quality
epithelial cell of pancreas	CL:0000083	93.70	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	78.21
E-HCAD-25	yes	54.35
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

112 targeting PDE8A, 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-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354

Literature-anchored findings (GeneRIF, showing 17)

• Comparison of enzymatic characterization and gene organization of PDE8B and PDE8A. (PMID:12681444)
• in vitro and in vivo experiments demonstrated that the association with IkappaB greatly enhanced the enzyme activity of PDE8A1 (PMID:15596729)
• kinetic properties of the highly active PDE8A1 catalytic domain prepared from refolding and its crystal structures in the unliganded and 3-isobutyl-1-methylxanthine (IBMX) bound forms at 1.9 and 2.1 A resolutions (PMID:18983167)
• The findings exclude a significant role for PDE8A as a PCOS candidate gene, and as a Las major determinant of androgen levels in women. (PMID:19482904)
• Polymorphism in PDE8A affects HIV-1 replication in primary macrophages. (PMID:21920574)
• PDE8 activity can be modulated by a kinase (PMID:22673573)
• PDE8A can bind tightly to Raf-1, regulate Raf-1 phosphorylation on S259, and, in so doing, regulate the cross-talk node whereby cAMP exerts an inhibitory effect on Raf-1 signaling, retarding subsequent ERK phosphorylation and activation. (PMID:23509299)
• a novel and critical role for phosphodiesterases in moderating local concentrations of cAMP in microdomains and signal resetting (PMID:25229150)
• PDE8A supports HIV-1 replication in macrophages (PMID:25295610)
• SNPs within genes SCHIP1 and PDE8A were associated with measures of facial size in both the GWAS and replication cohorts and passed a stringent genomewide significance threshold adjusted for multiple testing of 34 correlated traits. For both SCHIP1 and PDE8A, we demonstrated clear expression in the developing mouse face by both whole-mount in situ hybridization and RNA-seq (PMID:27560698)
• PDE8 is expressed in lipid rafts of human airway smooth muscle cells(HASM), where it specifically regulates beta2-adrenergic receptor/ AC6 signaling to modulate HASM responsiveness and airway remodeling in asthma. (PMID:29262264)
• Editing of PDE8A mRNA displayed clear regional difference when comparing dorsolateral prefrontal cortex (BA9) and anterior cingulate cortex (BA24). There were significant intra-regional differences between non-psychiatric control individuals and depressed suicide decedents. (PMID:30770787)
• Phosphodiesterase 8A to discriminate in blood samples depressed patients and suicide attempters from healthy controls based on A-to-I RNA editing modifications. (PMID:33931591)
• Phosphodiesterase 8A Regulates CFTR Activity in Airway Epithelial Cells. (PMID:34936285)
• cAMP-specific phosphodiesterase 8A and 8B isoforms are differentially expressed in human testis and Leydig cell tumor. (PMID:36277728)
• 14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway. (PMID:38325743)
• AKAP12 Upregulation Associates With PDE8A to Accelerate Cardiac Dysfunction. (PMID:38506047)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pde8a	ENSDARG00000087941
mus_musculus	Pde8a	ENSMUSG00000025584
rattus_norvegicus	Pde8a	ENSRNOG00000019005
drosophila_melanogaster	Pde11	FBGN0085370
drosophila_melanogaster	Pde8	FBGN0266377
caenorhabditis_elegans		WBGENE00008443
caenorhabditis_elegans	pde-6	WBGENE00022389

Paralogs (20): PDE4A (ENSG00000065989), PDE6C (ENSG00000095464), PDE4C (ENSG00000105650), PDE10A (ENSG00000112541), PDE8B (ENSG00000113231), PDE4D (ENSG00000113448), 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

High affinity cAMP-specific and IBMX-insensitive 3’,5’-cyclic phosphodiesterase 8A — O60658 (reviewed: O60658)

All UniProt accessions (4): O60658, E9PIJ0, H0YKR1, H0YNP3

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in maintaining basal levels of the cyclic nucleotide and/or in the cAMP regulation of germ cell development. Binding to RAF1 reduces RAF1 ‘Ser-259’ inhibitory-phosphorylation and stimulates RAF1-dependent EGF-activated ERK-signaling. Protects against cell death induced by hydrogen peroxide and staurosporine.

Subunit / interactions. Interacts with RAF1. The interaction promotes RAF1 activity.

Tissue specificity. Expressed in most tissues except thymus and peripheral blood leukocytes. Highest levels in testis, ovary, small intestine and colon.

Post-translational modifications. Phosphorylated at Ser-359 by PKA under elevated cAMP conditions, this enhances catalytic activity.

Activity regulation. Inhibited by dipyridimole. Insensitive to selective PDE inhibitors including rolipram and zaprinast as well as to the non-selective inhibitor, IBMX. Unaffected by cGMP.

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

Domain organisation. Composed of a C-terminal catalytic domain containing two putative divalent metal sites and an N-terminal regulatory domain.

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

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the cyclic nucleotide phosphodiesterase family. PDE8 subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
O60658-1	1, PDE8A1	yes
O60658-2	2, PDE8A2
O60658-3	3, PDE8A3
O60658-4	4, PDE8A4
O60658-5	5, PDE8A5
O60658-6	6

RefSeq proteins (3): NP_001230066, NP_002596, NP_775656 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR002073	PDEase_catalytic_dom	Domain
IPR003607	HD/PDEase_dom	Domain
IPR013767	PAS_fold	Domain
IPR023088	PDEase	Family
IPR023174	PDEase_CS	Conserved_site
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036971	PDEase_catalytic_dom_sf	Homologous_superfamily
IPR057304	PDE8-like_REC_N	Domain

Pfam: PF00233, PF00989, PF08629, PF23198

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 (64 total): helix 23, splice variant 8, turn 6, binding site 5, modified residue 5, domain 3, mutagenesis site 3, sequence conflict 3, region of interest 3, strand 2, chain 1, sequence variant 1, active site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3ECM	X-RAY DIFFRACTION	1.9
3ECN	X-RAY DIFFRACTION	2.1
8YTA	X-RAY DIFFRACTION	2.5
7VSL	X-RAY DIFFRACTION	2.5
7VTX	X-RAY DIFFRACTION	2.5
7VTW	X-RAY DIFFRACTION	2.8
7CWA	X-RAY DIFFRACTION	2.8
7CWF	X-RAY DIFFRACTION	2.8
7CWG	X-RAY DIFFRACTION	2.8
7VTV	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60658-F1	78.51	0.52

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): 556 (proton donor)

Ligand- & substrate-binding residues (5): 597; 597; 726; 560; 596

Post-translational modifications (5): 20, 359, 386, 457, 461

Mutagenesis-validated functional residues (3):

Position	Phenotype
454–455	reduces interaction with raf1; when associated with a-460 and a-461.
460–461	reduces interaction with raf1; when associated with a-454 and a-455.
748	increases sensitivity to several nonselective or family selective pde inhibitors.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 305 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOLDRATH_IMMUNE_MEMORY, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_EPIDERMAL_GROWTH_FACTOR, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOMF_KINASE_ACTIVATOR_ACTIVITY

GO Biological Process (6): cAMP catabolic process (GO:0006198), regulation of DNA-templated transcription (GO:0006355), signal transduction (GO:0007165), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to epidermal growth factor stimulus (GO:0071364), negative regulation of cAMP/PKA signal transduction (GO:0141162)

GO Molecular Function (8): 3’,5’-cyclic-AMP phosphodiesterase activity (GO:0004115), kinase binding (GO:0019900), protein kinase activator activity (GO:0030295), metal ion binding (GO:0046872), 3’,5’-cyclic-GMP phosphodiesterase activity (GO:0047555), 3’,5’-cyclic-nucleotide phosphodiesterase activity (GO:0004114), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787)

GO Cellular Component (2): cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
3’,5’-cyclic-nucleotide phosphodiesterase activity	2
purine ribonucleotide catabolic process	1
cyclic nucleotide catabolic process	1
cAMP metabolic process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
response to epidermal growth factor	1
cellular response to growth factor stimulus	1
cAMP/PKA signal transduction	1
regulation of cAMP/PKA signal transduction	1
negative regulation of intracellular signal transduction	1
enzyme binding	1
protein kinase activity	1
kinase activator activity	1
protein kinase regulator activity	1
cation binding	1
cyclic-nucleotide phosphodiesterase activity	1
phosphoric ester hydrolase activity	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

448 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE8A	ALDH7A1	P49419	842
PDE8A	MACC1	Q6ZN28	622
PDE8A	IARS1	P41252	532
PDE8A	SMIM23	A6NLE4	479
PDE8A	AKAP1	Q92667	478
PDE8A	LDLRAD3	Q86YD5	447
PDE8A	NFKBIB	Q15653	442
PDE8A	PRKAR1A	P10644	427
PDE8A	ENOSF1	Q7L5Y1	406
PDE8A	OLA1	Q9NTK5	392
PDE8A	IQCJ-SCHIP1	B3KU38	384
PDE8A	F8WDG0	F8WDG0	384
PDE8A	PDIA2	Q13087	383
PDE8A	GOSR1	O95249	380
PDE8A	PDE4A	P27815	373

IntAct

14 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
UNC119	UNC119B	psi-mi:“MI:0914”(association)	0.640
UNC119	PDE8A	psi-mi:“MI:0914”(association)	0.530
PDE8B	PDE8A	psi-mi:“MI:0915”(physical association)	0.400
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
ZBTB18	DNASE1L1	psi-mi:“MI:0914”(association)	0.350
TRIB1	PDE8A	psi-mi:“MI:0914”(association)	0.350
KCNK3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
NPHP3	PDE8A	psi-mi:“MI:0915”(physical association)	0.000
msbA	PDE8A	psi-mi:“MI:0915”(physical association)	0.000
PDE8A	sbcD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): PDE8A (Affinity Capture-MS), PDE8A (Affinity Capture-MS), PDE8A (Affinity Capture-MS), PDE8A (Affinity Capture-MS), PDE8A (Affinity Capture-RNA), PDE8A (Synthetic Lethality), PDE8A (Proximity Label-MS), PDE8A (Proximity Label-MS), PDE8A (Proximity Label-MS), PDE8A (Proximity Label-MS), PDE8A (Affinity Capture-RNA), PDE8A (Proximity Label-MS), PDE8A (Proximity Label-MS), PDE8A (Proximity Label-MS), PDE8A (Proximity Label-MS)

ESM2 similar proteins: B3LVW5, B3P3K2, B4G4E5, B4HEM4, B4JXX2, B4K9L4, B4LVU6, B4NAL6, B4PSS5, B4QZU1, E9Q4S1, O18696, O18965, O54735, O60658, O76074, O77746, O88502, O95259, O95263, P0C1Q2, P11541, P16499, P16586, P23439, P23440, P27664, P33726, P35913, P51160, P52731, P91119, Q01062, Q02280, Q07093, Q1KKS3, Q28156, Q28263, Q298P4, Q60603

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, B0G0Y8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PKA	“up-regulates activity”	PDE8A	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	103
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4547 predictions. Top by Δscore:

Variant	Effect	Δscore
15:85064422:TTCAG:T	donor_loss	1.0000
15:85064423:TCAGG:T	donor_loss	1.0000
15:85064424:CAG:C	donor_loss	1.0000
15:85064425:AGG:A	donor_loss	1.0000
15:85064426:GGTAA:G	donor_loss	1.0000
15:85064427:G:T	donor_loss	1.0000
15:85064428:T:A	donor_loss	1.0000
15:85083554:A:AG	acceptor_gain	1.0000
15:85083555:G:GG	acceptor_gain	1.0000
15:85089334:A:AG	acceptor_gain	1.0000
15:85089334:AAAG:A	acceptor_gain	1.0000
15:85089334:AAAGG:A	acceptor_gain	1.0000
15:85089335:AAG:A	acceptor_gain	1.0000
15:85089336:AG:A	acceptor_gain	1.0000
15:85089337:GG:G	acceptor_gain	1.0000
15:85113375:A:AG	acceptor_gain	1.0000
15:85113376:G:GG	acceptor_gain	1.0000
15:85115426:T:A	acceptor_gain	1.0000
15:85115437:AGGAT:A	acceptor_gain	1.0000
15:85115438:GGATG:G	acceptor_gain	1.0000
15:85115488:G:GG	donor_gain	1.0000
15:85115488:GTAA:G	donor_loss	1.0000
15:85115489:T:A	donor_loss	1.0000
15:85120796:GGAAA:G	acceptor_gain	1.0000
15:85121010:GAGAG:G	donor_gain	1.0000
15:85121012:GAG:G	donor_gain	1.0000
15:85121014:GGTA:G	donor_loss	1.0000
15:85121015:G:A	donor_loss	1.0000
15:85121015:G:GG	donor_gain	1.0000
15:85126371:TCAGG:T	donor_loss	1.0000

AlphaMissense

5496 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:85113952:T:C	L422P	1.000
15:85117771:C:G	H556D	1.000
15:85120852:A:T	D597V	1.000
15:85126339:T:A	W740R	1.000
15:85126339:T:C	W740R	1.000
15:85136621:T:C	F781L	1.000
15:85136623:C:A	F781L	1.000
15:85136623:C:G	F781L	1.000
15:85137850:T:A	W813R	1.000
15:85137850:T:C	W813R	1.000
15:85113895:C:A	A403D	0.999
15:85113952:T:A	L422Q	0.999
15:85116076:T:A	W498R	0.999
15:85116076:T:C	W498R	0.999
15:85117726:T:A	W541R	0.999
15:85117726:T:C	W541R	0.999
15:85117773:C:A	H556Q	0.999
15:85117773:C:G	H556Q	0.999
15:85117799:T:C	L565P	0.999
15:85120840:C:A	A593D	0.999
15:85120848:C:G	H596D	0.999
15:85120852:A:C	D597A	0.999
15:85120860:C:G	H600D	0.999
15:85120861:A:G	H600R	0.999
15:85120862:C:A	H600Q	0.999
15:85120862:C:G	H600Q	0.999
15:85120881:T:C	F607L	0.999
15:85120883:C:A	F607L	0.999
15:85120883:C:G	F607L	0.999
15:85120917:T:G	Y619D	0.999

dbSNP variants (sampled 300 via entrez): RS1000022580 (15:85053495 G>A,C), RS1000044562 (15:85056304 G>A,C,T), RS1000079373 (15:85018361 T>G), RS1000105065 (15:84986244 A>G), RS1000106553 (15:85065268 C>G), RS1000107319 (15:85103801 C>G,T), RS1000119788 (15:85132264 G>A,C,T), RS1000120648 (15:85117286 G>A), RS1000126090 (15:85133900 G>A), RS1000148488 (15:85089130 A>C,G), RS1000151701 (15:85123839 T>A), RS1000157961 (15:85025362 C>T), RS1000165286 (15:85120360 C>A,T), RS1000182376 (15:85092322 G>A,T), RS1000192396 (15:85007647 G>A,C)

Disease associations

OMIM: gene MIM:602972 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000775_1	Central corneal thickness	1.000000e-08
GCST001958_3	Bulimia nervosa	3.000000e-06
GCST004635_29	Testicular germ cell tumor	5.000000e-08
GCST006624_27	Systolic blood pressure	1.000000e-15
GCST006979_939	Heel bone mineral density	2.000000e-27
GCST007267_198	Systolic blood pressure	3.000000e-08
GCST007928_24	Medication use (diuretics)	4.000000e-09
GCST008821_2	Neurofibrillary tangles	9.000000e-06
GCST008839_222	Height	2.000000e-14
GCST012226_542	Waist circumference adjusted for body mass index	3.000000e-08
GCST90020028_1443	Hip circumference adjusted for BMI	5.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004731	eye measurement
EFO:0006335	systolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0009928	Diuretic use measurement
EFO:0006797	neurofibrillary tangles measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2363066 (PROTEIN FAMILY), CHEMBL2363067 (PROTEIN FAMILY), CHEMBL4640 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 93,588 (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
CHEMBL192	SILDENAFIL	4	41,819
CHEMBL932	DIPYRIDAMOLE	4	51,743
CHEMBL2180408	JNJ-42396302	1	12
CHEMBL3770459	LENRISPODUN PHOSPHATE	1	14

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

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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
PF-04957325	Inhibition	7.37	pIC50
dipyridamole	Inhibition	5.1	pIC50

Binding affinities (BindingDB)

10 measured of 24 human assays (24 total across all organisms); most potent 10 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Dipyridamine	KI	8.18 nM
5-[[6-(1,3-difluoropropan-2-yloxy)-1-(1-formylpiperidin-4-yl)-2,4-dioxo-4a,5,6,7,8,8a-hexahydroquinazolin-3-yl]methyl]-2-phenylbenzonitrile	IC50	37 nM	US-8846654: Therapeutic applications in the cardiovascular field of quinazolinedione derivatives
4-[6-(1,3-difluoropropan-2-yloxy)-3-[(3,4-dimethoxyphenyl)methyl]-2,4-dioxo-4a,5,6,7,8,8a-hexahydroquinazolin-1-yl]piperidine-1-carbaldehyde	IC50	39 nM	US-8846654: Therapeutic applications in the cardiovascular field of quinazolinedione derivatives
4-[6-(1,3-difluoropropan-2-yloxy)-3-[[3-methoxy-4-(2-oxo-2-piperidin-1-ylethoxy)phenyl]methyl]-2,4-dioxo-4a,5,6,7,8,8a-hexahydroquinazolin-1-yl]piperidine-1-carbaldehyde	IC50	46 nM	US-8846654: Therapeutic applications in the cardiovascular field of quinazolinedione derivatives
2-{2-ethoxy-5-[(4-ethylpiperazine-1-)sulfonyl]phenyl}-5-methyl-7-propyl-3H,4H-imidazo[1,5-a][1,2,4]triazin-4-one	IC50	300 nM
SILDENAFIL CITRATE	IC50	1500 nM
(6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1,2,1,6]pyrido[3,4-b]indole-1,4-dione	IC50	50000 nM
3-(cyclopentyloxy)-N-(3,5-dichloropyridin-4-yl)-4-methoxybenzamide	IC50	68000 nM
Ariflo	IC50	87000 nM
(E)-{1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethylidene}amino carbamate	IC50	190000 nM

ChEMBL bioactivities

55 potent at pChembl≥5 of 63 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL5081214
9.90	IC50	0.1259	nM	CHEMBL5080391
9.80	IC50	0.1585	nM	CHEMBL5087564
9.60	IC50	0.2512	nM	CHEMBL5094110
9.50	IC50	0.3162	nM	CHEMBL5086895
9.50	IC50	0.3162	nM	CHEMBL5076558
9.15	IC50	0.7	nM	CHEMBL5169811
9.00	IC50	1	nM	CHEMBL5078680
9.00	IC50	1	nM	CHEMBL5088742
9.00	IC50	1	nM	CHEMBL5285855
8.74	IC50	1.8	nM	CHEMBL1779976
8.74	IC50	1.8	nM	CHEMBL1779978
8.74	IC50	1.8	nM	CHEMBL1779984
8.72	IC50	1.9	nM	CHEMBL2070735
8.72	IC50	1.9	nM	CHEMBL5723345
8.00	IC50	10	nM	CHEMBL4762103
7.82	IC50	15	nM	CHEMBL3646900
7.58	IC50	26	nM	CHEMBL4753446
7.34	IC50	46	nM	CHEMBL4790482
6.89	IC50	130	nM	CHEMBL4800434
6.85	IC50	140	nM	CHEMBL3646893
6.71	IC50	194	nM	CHEMBL5407967
6.66	IC50	220	nM	CHEMBL4789101
6.62	IC50	240	nM	CHEMBL4778928
6.60	IC50	250	nM	CHEMBL4798107
6.60	IC50	250	nM	CHEMBL4745958
6.55	IC50	280	nM	CHEMBL5288859
6.48	IC50	330	nM	CHEMBL5434573
6.44	IC50	360	nM	CHEMBL4757863
6.41	IC50	390	nM	CHEMBL3646899
6.39	IC50	410	nM	CHEMBL4747327
6.18	IC50	660	nM	CHEMBL4750412
6.15	IC50	710	nM	CHEMBL4877549
6.09	IC50	820	nM	CHEMBL5171560
6.04	IC50	920	nM	CHEMBL4786234
6.00	IC50	1000	nM	CHEMBL92216
5.89	IC50	1275	nM	CHEMBL6162994
5.83	IC50	1490	nM	CHEMBL5306577
5.76	IC50	1716	nM	CHEMBL6193335
5.75	IC50	1760	nM	CHEMBL5532056
5.70	IC50	2000	nM	CHEMBL91789
5.69	IC50	2022	nM	CHEMBL4644729
5.55	IC50	2800	nM	CHEMBL4790086
5.52	Ki	3000	nM	LENRISPODUN PHOSPHATE
5.52	IC50	3000	nM	CHEMBL3919436
5.45	IC50	3560	nM	CHEMBL4075951
5.40	IC50	4000	nM	DIPYRIDAMOLE
5.29	IC50	5164	nM	CHEMBL6167402
5.21	IC50	6223	nM	CHEMBL4099219
5.12	IC50	7576	nM	CHEMBL6162075

PubChem BioAssay actives

47 with measured affinity, of 313 total; 43 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
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]sulfamoyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[N-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxycarbonyl]anilino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0001	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0002	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]sulfamoyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
3-[[(2R)-4-(1,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl]-5-(trifluoromethyl)triazolo[4,5-d]pyrimidin-7-amine	1872584: Inhibition of PDE8A (unknown origin)	ic50	0.0007	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[N-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxycarbonyl]anilino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0010	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0010	uM
1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]piperidine-3-carboxamide	598329: Inhibition of PDE8A	ic50	0.0018	uM
(3R,5R)-5-ethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]piperidine-3-carboxamide	598329: Inhibition of PDE8A	ic50	0.0018	uM
2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]-3,4-dihydro-1H-isoquinoline-4-carboxamide	598329: Inhibition of PDE8A	ic50	0.0018	uM
5-methyl-3-[[(2R)-4-(1,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl]triazolo[4,5-d]pyrimidin-7-amine	677941: Inhibition of PDE8A	ic50	0.0019	uM
2-chloro-9-[(1S)-1-[4-(2,2-difluoroethoxy)-2-pyridinyl]ethyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.0100	uM
2-chloro-9-[1-[4-(2,2-difluoroethoxy)-2-pyridinyl]ethyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.0260	uM
2-chloro-9-[(6-cyclopentyl-2-pyridinyl)methyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.0460	uM
2-chloro-9-[[6-(2-fluorophenyl)-2-pyridinyl]methyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.1300	uM
9-(cyclopropylmethoxy)-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-enyl)-5-(pyridin-4-ylmethoxy)pyrano[3,2-b]xanthen-6-one	1986518: Inhibition of recombinant PDE8A1 (480 to 828 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]cAMP as substrate incubated for 15 mins by liquid scintillation method	ic50	0.1940	uM
2-chloro-9-[[6-(oxan-4-yl)-2-pyridinyl]methyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.2200	uM
2-chloro-9-[[6-(furan-2-yl)-2-pyridinyl]methyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.2400	uM
2-chloro-9-[[6-(3,6-dihydro-2H-pyran-4-yl)-2-pyridinyl]methyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.2500	uM
2-chloro-9-[[6-(cyclopenten-1-yl)-2-pyridinyl]methyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.2500	uM
3-[(3-ethyl-[1,2,4]triazolo[4,3-c]quinazolin-5-yl)amino]benzoic acid	1923576: Inhibition of PDE8A (unknown origin) using cAMP as substrate incubated for 30 mins by Ba(OH)2 precipitation assay based scintillation counter	ic50	0.2800	uM
N-(2-pyrazin-2-yl-4,6-dihydrothieno[3,4-c]pyrazol-3-yl)naphthalene-1-carboxamide	1994821: Inhibition of PDE (unknown origin)	ic50	0.3300	uM
2-chloro-9-[[4-(2,2-difluoroethoxy)-2-pyridinyl]methyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.3600	uM
2-chloro-9-[(4-chloro-2-pyridinyl)methyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.4100	uM
Dipyridamole	1799753: Enzymatic Assay from Article 10.1074/jbc.M111.326777: “Biological and structural characterization of Trypanosoma cruzi phosphodiesterase C and Implications for design of parasite selective inhibitors.”	ic50	0.5000	uM
2-chloro-9-[(4-methoxy-2-pyridinyl)methyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.6600	uM
(E)-4-[9-[(4-fluorophenyl)methoxy]-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-enyl)-6-oxopyrano[3,2-b]xanthen-5-yl]oxybut-2-enoic acid	1773997: Inhibition of PDE8A1 (480-828) (unknown origin) expressed in Escherichia coli BL21 assessed as using [3H]-cAMP as substrate measured for 15 mins by liquid scintillation counting analysis	ic50	0.7100	uM
(2R,4S)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-enyl)-3,4-dihydropyrano[3,2-c][1,8]naphthyridin-5-one	1902939: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H-GMP] or [3H-AMP] as substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.8200	uM
2-chloro-9-[[6-(2,2-difluoroethoxy)-2-pyridinyl]methyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	0.9200	uM
3-ethyl-2,4,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5,10,12-pentaen-7-one	1859268: Inhibition of cAMP-specific 3’,5’-cyclic phosphodiesterase (unknown origin)	ic50	1.0000	uM
cyclohexylmethyl 3-benzylsulfanylcarbonyl-4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-6-methyl-2-oxo-1,4-dihydropyrimidine-5-carboxylate	2070784: Inhibition of PDE8A (480 to 820 residues) (unknown origin) using 3H-cAMP as substrate	ic50	1.7600	uM
1-ethyl-3-methyl-5H-imidazo[1,5-a]quinoxalin-4-one	1859268: Inhibition of cAMP-specific 3’,5’-cyclic phosphodiesterase (unknown origin)	ic50	2.0000	uM
1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[5,4-d]pyrimidin-4-one	1652902: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method relative to control	ic50	2.0220	uM
2-chloro-9-[(1R)-1-[4-(2,2-difluoroethoxy)-2-pyridinyl]ethyl]purin-6-amine	1701400: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) expressed in Escherichia coli BL21 using [3H]-cAMP substrate incubated for 15 mins by liquid scintillation counting method	ic50	2.8000	uM
(11R,15S)-5-anilino-4-[[4-(6-fluoro-2-pyridinyl)phenyl]methyl]-8-methyl-1,3,4,8,10-pentazatetracyclo[7.6.0.02,6.011,15]pentadeca-2,5,9-trien-7-one;phosphoric acid	1281083: Inhibition of recombinant full lenght human PDE8A using fluorescent labeled cAMP as substrate after 15 mins by IMAP assay	ki	3.0000	uM
4-[8-morpholin-4-yl-2-[(E)-2-quinolin-2-ylethenyl]imidazo[1,2-b]pyridazin-3-yl]benzoic acid	1636993: Inhibition of human PDE	ic50	3.0000	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] (2S)-3-[3-(dimethylcarbamoyl)phenyl]sulfonyl-1,3-thiazolidine-2-carboxylate	1472216: Inhibition of human recombinant PDE8A1 expressed insect sf9 cells by radiometric assay	ic50	3.5600	uM
3-(1,3-benzodioxol-5-ylmethyl)-1-(1,3-thiazol-2-yl)-2H-chromeno[2,3-c]pyrrol-9-one	1446367: Inhibition of PDE8A1 (480 to 820 residues) (unknown origin) using [3H]cGMP or [3H]cAMP as substrate after 15 mins by liquid scintillation counting method	ic50	6.2230	uM
4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid	1797296: Phosphodiesterase (PDE) Inhibition Assay from Article 10.1016/j.str.2004.10.004: “Structural basis for the activity of drugs that inhibit phosphodiesterases.”	ic50	7.0000	uM
(11R,15S)-5-anilino-8-methyl-4-[(4-pyridin-2-ylphenyl)methyl]-1,3,4,8,10-pentazatetracyclo[7.6.0.02,6.011,15]pentadeca-2,5,9-trien-7-one	1281083: Inhibition of recombinant full lenght human PDE8A using fluorescent labeled cAMP as substrate after 15 mins by IMAP assay	ki	8.2000	uM
8-[(2-fluoro-4-methoxyphenyl)methyl]-13-(oxan-4-ylmethyl)-10-thia-3,5,6,8,13-pentazatetracyclo[7.7.0.02,6.011,16]hexadeca-1(9),2,4,11(16)-tetraen-7-one	1443931: Inhibition of N-terminal GST-tagged full length recombinant human PDE8A1 expressed in Baculovirus infected Sf9 insect cells assessed as decrease in FAM-cAMP hydrolysis after 1 hr by fluorescence polarization assay	ic50	8.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, increases expression, affects expression	7
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	4
Arsenic	increases abundance, increases expression, decreases expression, affects methylation, affects cotreatment	3
perfluorooctane sulfonic acid	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	affects methylation	1
salinomycin	decreases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression, increases expression	1
potassium chromate(VI)	decreases expression	1
coumarin	increases phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
E 4021	decreases reaction, increases metabolic processing	1
CGP 52608	increases reaction, affects binding	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	increases expression	1
Cidofovir	decreases expression	1
Acrolein	increases abundance, affects cotreatment, decreases expression	1
Cyclic AMP	decreases reaction, increases metabolic processing	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Vehicle Emissions	affects expression, increases abundance	1
Caffeine	decreases phosphorylation	1

ChEMBL screening assays

137 unique, capped per target: 129 binding, 6 admet, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4479636	Binding	Inhibition of human PDE	Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors. — Bioorg Med Chem Lett
CHEMBL4680008	ADMET	Inhibition of PDE (unknown origin)	Fragment-Based Discovery of Novel Allosteric MEK1 Binders. — ACS Med Chem Lett
CHEMBL5723184	Functional	Affinity Biochemical interaction: (inhibition of enzyme activity with [3H]cGMP or [3H]cAMP as the substrate) EUB0002477a PDE8A	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TC71	HAP1 PDE8A (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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