PDE4A

Summary

PDE4A (phosphodiesterase 4A, HGNC:8780) is a protein-coding gene on chromosome 19p13.2, encoding 3’,5’-cyclic-AMP phosphodiesterase 4A (P27815). Hydrolyzes the second messenger 3’,5’-cyclic AMP (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 PDE4 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 described for this gene.

Source: NCBI Gene 5141 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 97 total
• Druggable target: yes — 147 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001111307

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8780
Approved symbol	PDE4A
Name	phosphodiesterase 4A
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000065989
Ensembl biotype	protein_coding
OMIM	600126
Entrez	5141

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000293683, ENST00000344979, ENST00000380702, ENST00000440014, ENST00000586275, ENST00000589073, ENST00000590407, ENST00000591971, ENST00000592685, ENST00000875632, ENST00000937030, ENST00000937031

RefSeq mRNA: 5 — MANE Select: NM_001111307 NM_001111307, NM_001111308, NM_001111309, NM_001243121, NM_006202

CCDS: CCDS12238, CCDS45961, CCDS45962, CCDS45963, CCDS58649

Canonical transcript exons

ENST00000380702 — 15 exons

Exon	Start	End
ENSE00000954037	10420538	10421084
ENSE00001060817	10459400	10459498
ENSE00001133719	10450829	10450941
ENSE00001133723	10450603	10450652
ENSE00001382781	10466887	10469630
ENSE00001599570	10446218	10446409
ENSE00001693691	10449080	10449150
ENSE00001736027	10448917	10448953
ENSE00003523998	10461877	10461999
ENSE00003529707	10461004	10461103
ENSE00003578033	10454829	10454922
ENSE00003595988	10457879	10458102
ENSE00003642068	10459595	10459759
ENSE00003671956	10461526	10461680
ENSE00003692346	10463793	10463975

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 90.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.0160 / max 193.6761, expressed in 1410 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173804	2.7349	121
173802	2.5347	974
173797	2.5239	484
173801	0.9727	557
173800	0.2416	110
173796	0.0082	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	90.76	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.47	gold quality
parietal lobe	UBERON:0001872	90.42	gold quality
postcentral gyrus	UBERON:0002581	90.38	gold quality
primary visual cortex	UBERON:0002436	89.84	gold quality
occipital lobe	UBERON:0002021	89.48	gold quality
superior frontal gyrus	UBERON:0002661	88.69	gold quality
right frontal lobe	UBERON:0002810	88.57	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.14	gold quality
cingulate cortex	UBERON:0003027	87.97	gold quality
anterior cingulate cortex	UBERON:0009835	87.81	gold quality
apex of heart	UBERON:0002098	87.77	gold quality
cerebellar vermis	UBERON:0004720	87.12	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.07	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.03	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.79	gold quality
muscle of leg	UBERON:0001383	86.66	gold quality
orbitofrontal cortex	UBERON:0004167	86.61	gold quality
gastrocnemius	UBERON:0001388	86.60	gold quality
entorhinal cortex	UBERON:0002728	86.37	gold quality
left testis	UBERON:0004533	86.34	gold quality
right testis	UBERON:0004534	86.22	gold quality
pons	UBERON:0000988	86.13	gold quality
muscle organ	UBERON:0001630	86.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.13	gold quality
neocortex	UBERON:0001950	86.10	gold quality
stromal cell of endometrium	CL:0002255	85.97	gold quality
frontal cortex	UBERON:0001870	85.97	gold quality
middle temporal gyrus	UBERON:0002771	85.93	gold quality
cerebellar cortex	UBERON:0002129	85.71	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.28
E-MTAB-7303	no	203.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

134 targeting PDE4A, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-369-3P	99.85	70.52	2264

Literature-anchored findings (GeneRIF, showing 40)

• PDE4A10 is a long form splice variant of the human cAMP phosphodiesterase PDE4A gene. PDE4A10 was localized primarily to the perinuclear region of COS7 cells. (PMID:11306681)
• purification and characterization of recombinant proteins from E coli and Sf9 cells (PMID:11566027)
• Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia (PMID:11839681)
• In vitro phosphorylation of PDE4A4 by the PKA-catalytic subunit increases the enzyme’s sensitivity to Mg(2+), leading to 4-fold increased cAMP hydrolysis without affecting its K(m). (PMID:11852080)
• An 11-residue helical module in the N-terminal region of PDE4A1 determines the association with phospholipid bilayers and shows a profound selectivity for interaction with phosphatidic acid. (PMID:11994273)
• Results suggest that type 4A cAMP-specific phosphodiesterase may downregulate cyclic AMP signaling at the cell membrane and/or in the extracellular space at the time of granule release. (PMID:12764607)
• The immunophilin AIP (XAP2/ARA9) reversibly inhibited the enzymatic activity of PDE4A5, an isoform of PDE4A. (PMID:12810716)
• PDE4A4 is specifically up-regulated in macrophages from smokers with chronic obstructive pulmonary disease (COPD) and may provide a specific therapeutic target. (PMID:15047569)
• PDE4A11 is a novel, widely expressed long isoform that is activated by protein kinase A phosphorylation, shows a distinct intracellular localization, and may contribute to compartmentalized cyclic AMP signaling in cells in which it is expressed. (PMID:15738310)
• Keynote review: phosphodiesterase-4 as a therapeutic target (PMID:16257373)
• In this review, the fundamental biological role of PDE4 in intracellular signalling, its tissue distribution and regulation are described. (PMID:16300476)
• The N-terminal region unique to PDE4A1 consists of two well-defined helical regions separated by a mobile hinge region. Helix-2 provides the core membrane-insertion module and helix-1 facilitates membrane association. (PMID:16856845)
• The unique N-terminal region of PDE4A1 consists of two helices, where Helix-1 regulates the phospholipase-D-dependent redistribution of PDE4A1 in response to release of Ca2+, providing a unique link between these signalling pathways (PMID:16940352)
• PDE4A4 interacts with the p75 neurotropin receptor to enhance cAMP degradation and block fibrinolysis by down-regulating tissue plasminogen activator and so perpetuating scar formation after sciatic nerve and lung injury (PMID:17576803)
• unique tissue distribution of PDE4A8, combined with the evolutionary divergence of its N-terminus, suggest that this isoform may have a specific function in regulating cAMP levels in human skeletal muscle and brain (PMID:18095939)
• observed that specific isoforms of PDE4A were reduced in cerebella of patients with bipolar disorder, whereas there was no change in patients with schizophrenia or major depression (PMID:19018233)
• PDE4 is widely expressed in brain tumors and promotes their growth (PMID:19047098)
• The results suggest that brain-derived neurotrophic factor/TrkB and cAMP phosphodiesterase-4, but not the gastrin-releasing peptide receptor, regulate the viability of medulloblastoma cells. (PMID:19642024)
• Results suggest that TGF-beta1 mediated up-regulation of phosphodiesterase 4 promotes epithelial-mesenchymal transition in alveolar epithelial cells. (PMID:19759179)
• Inhibition of PDE4 inhibition (rather than PDE3) may diminish proliferation of human lung fibroblasts and therefore could be useful in the therapy of pathological remodeling in lung diseases. (PMID:20082309)
• Data show that PI3K activation and PIP3 production lead to recruitment of the PKB/beta-arrestin/PDE4 complex to the membrane via the PKB PH domain, resulting in degradation of the TCR-induced cAMP pool and allowing full T-cell activation to proceed. (PMID:20086095)
• GSK256066 demonstrated a protective effect on the EAR and LAR. (PMID:20193079)
• Data show that inhibition of PA hydrolysis provokes internalization of inactive EGFR, accompanied by a transient increase in PA levels and PDE4s activity. (PMID:20554760)
• The results of this study suggested that apPDE4s can participate in the regulation of cAMP signaling through specific subcellular localization by means of lipid binding activities. (PMID:20813835)
• PDE4 expression is reduced in failing human heart. PDE4 affects local but not global cAMP levels in human cardiomyocytes. (PMID:21161247)
• we have identified a so-far-unknown interaction between LIS1 and PDE4 isoforms, whereby PDE4 can modulate LIS1-dynein complexes and dynein-dependent processes within cells by sequestering LIS1. (PMID:21652625)
• Data demonstrate that upregulation of Nox4 leads to an upregulation of PDE4A, B, and D and increased hydrolysis of cAMP which in turn augments cell replication and angiogenesis. (PMID:21732365)
• These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population. (PMID:21898905)
• The hPDE4 long isoforms are activated by phosphorylation of a serine located in a conserved RRESF motif in a tandem of N-terminal upstream-conserved regions (UCR). (PMID:22484154)
• In phosphoinositide 3-kinasegamma-deficient cardiomyocytes, coincident signaling of the major cardiac PDE3 and PDE4 isoforms orchestrates a feedback loop that prevents calcium-dependent ventricular arrhythmia. (PMID:23008439)
• PDE4A and PDE4C work in redundant fashion to mediate the loss of inhibitory PGE2 signaling in lung fibroblasts. (PMID:23043089)
• long-acting beta -agonist and PDE4 inhibitor have a synergistic effect in regulating fibroblast tissue repair functions and PGE2 can modulate the effect of beta -agonist and PDE4 inhibitor at least in part through the mechanism of regulating PDE4 expression (PMID:24227907)
• Hydroxycarbamide decreases sickle reticulocyte adhesion to resting endothelium by inhibiting endothelial lutheran/basal cell adhesion molecule (Lu/BCAM) through phosphodiesterase 4A activation. (PMID:24616094)
• AKAP 149-PKA-PDE4A complex localization is related with YTX effect in K-562 cell line (PMID:24813785)
• curcumin exerts its in vitro anti-angiogenic and in vivo anti-tumour properties through combined PDE2 and PDE4 inhibition (PMID:25230992)
• After 48 h yessotoxin treatment PDE4A-dependent autophagy, as non-apoptotic programmed cell death, is activated. (PMID:25576684)
• The expression of PDE4A4 and PDE4A8 in normal pituitary, their increased expression in adenomatous pituitary cells where AIP is meant to participate, and the disruption of the PDE4A4-AIP interaction by AIP mutants may play a role in pituitary tumorigenesis. (PMID:27267386)
• Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is safe, suppresses the oncogenic PI3K/AKT kinases, and may be clinically active (PMID:27542768)
• A multifunctional docking site on the catalytic unit of PDE4 that is utilized by multiple interaction partners has been identified. (PMID:27993970)
• Low PDE4A expression is associated with sepsis. (PMID:28356347)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pde4a	ENSDARG00000032344
mus_musculus	Pde4a	ENSMUSG00000032177
rattus_norvegicus	Pde4a	ENSRNOG00000020828
drosophila_melanogaster	Pde11	FBGN0085370
drosophila_melanogaster	Pde8	FBGN0266377
caenorhabditis_elegans		WBGENE00008443
caenorhabditis_elegans	pde-6	WBGENE00022389

Paralogs (20): PDE8A (ENSG00000073417), 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

3’,5’-cyclic-AMP phosphodiesterase 4A — P27815 (reviewed: P27815)

Alternative names: DPDE2, PDE46, cAMP-specific phosphodiesterase 4A

All UniProt accessions (3): P27815, K7EKV1, K7ENX7

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes the second messenger 3’,5’-cyclic AMP (cAMP), which is a key regulator of many important physiological processes. Efficiently hydrolyzes cAMP. Efficiently hydrolyzes cAMP. Efficiently hydrolyzes cAMP. The phosphodiesterase activity is not affected by calcium, calmodulin or cyclic GMP (cGMP) levels. Does not hydrolyze cGMP. Efficiently hydrolyzes cAMP. Efficiently hydrolyzes cAMP. Efficiently hydrolyzes cAMP.

Subunit / interactions. Interacts with LYN (via SH3 domain). Interacts with ARRB2. Interacts with LYN (via SH3 domain). Interacts with ARRB2. Interacts with LYN (via SH3 domain). Interacts with ARRB2.

Subcellular location. Cytoplasm. Perinuclear region Cytoplasm. Perinuclear region. Cell projection. Ruffle membrane Cytoplasm. Cytosol Membrane Cytoplasm. Cytosol. Membrane.

Tissue specificity. Expressed in lymphoid cell subsets including CD8-positive T cells and T-helper 2 cells. Expressed in dendritic cells. Highly expressed in liver, stomach, testis, thyroid and adrenal glands and at a lower extent in placenta, kidney, pancreas, ovary, uterus and skin. Expressed in myeloid cell subsets including dendritic cells, monocytes, macrophages, eosinophils and mast cells. Expressed in natural killer cells. Expressed in bronchial smooth muscle. Expressed at high levels in the heart and small intestine. It is also found in the brain, kidney, spleen, colon, salivary gland, ovary and peripheral blood lymphocytes. Expressed predominantly in skeletal muscle and brain and at lower levels in the testis. Found in specific neuronal subpopulations including cortical pyramidal neurons, horn neurons in the spinal cord and Purkinje cells in cerebellum (at protein level).

Post-translational modifications. Proteolytically cleaved by CASP3. Phosphorylated at Ser-119 by PKA.

Activity regulation. Inhibited by rolipram, cilomilast, Ro 20-1724, roflumilast and denbufylline. Inhibited by rolipram, cilomilast, Ro 20-1724, roflumilast and denbufylline. Inhibited by rolipram. Inhibited by rolipram. Inhibited by rolipram, cilomilast, Ro 20-1724, roflumilast and denbufylline. Inhibited by rolipram and cilomilast.

Cofactor. Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions. Binds 2 divalent metal cations per subunit (PubMed:17727341, Ref.20). 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. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Probably represents a non-functional splice isoform.

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

Isoforms (7)

UniProt ID	Names	Canonical?
P27815-1	1, PDE4A4, PDE4A4B, PDE46	yes
P27815-2	2, TM3, PDE4A11
P27815-3	3, PDE4A7, PDE4A6
P27815-4	4, PDE4A1, RD1
P27815-5	5, PDE4A8A, 2EL
P27815-6	6, PDE4A10
P27815-7	7, PDE4A8

RefSeq proteins (5): NP_001104777, NP_001104778, NP_001104779, NP_001230050, NP_006193 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002073	PDEase_catalytic_dom	Domain
IPR003607	HD/PDEase_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 3.1.4.17 — 3’,5’-cyclic-nucleotide phosphodiesterase (BRENDA: 27 organisms, 83 substrates, 296 inhibitors, 106 Km, 31 kcat entries)
• 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)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3’,5’-CAMP	0.0001–7	41
ADENOSINE 3’,5’-CYCLIC PHOSPHATE	—	34
3’,5’-CGMP	—	23
CAMP	0.0002–1.6	15
3’,5’-CAMP	0.0003–0.5	13
CGMP	0.0002–1	12
CAMP	0.0001–0.191	9
2’,3’-CAMP	0.0038–0.0052	2
5’-AMP	0.0014–0.0016	2
5’-ATP	0.0033–0.0125	2
CGMP	0.24–0.427	2
5’-PAPA	0.204	1
5’-PAPG	0.355	1
ADENOSINE 3’,5’-CYCLIC PHOSPHATE	0.012	1
GUANOSINE 3’,5’-CYCLIC PHOSPHATE	0.025	1

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (81 total): helix 22, binding site 16, modified residue 10, splice variant 8, turn 7, compositionally biased region 5, region of interest 4, sequence variant 2, strand 2, chain 1, domain 1, active site 1, site 1, cross-link 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3HC8	X-RAY DIFFRACTION	1.79
3HDZ	X-RAY DIFFRACTION	1.8
2QYK	X-RAY DIFFRACTION	2.1
3I8V	X-RAY DIFFRACTION	2.25
3TVX	X-RAY DIFFRACTION	2.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27815-F1	65.87	0.37

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 (2): 433 (proton donor); 69–70 (cleavage; by caspase-3)

Ligand- & substrate-binding residues (16): 433; 433; 437; 437; 473; 474; 474; 474; 474; 474; 591; 591 …

Post-translational modifications (11): 13, 152, 157, 165, 209, 346, 686, 688, 358, 119, 123

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-180024	DARPP-32 events
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 269 (showing top): AGGAAGC_MIR5163P, AAGCAAT_MIR137, AAGCCAT_MIR135A_MIR135B, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, GOCC_RUFFLE, GOBP_CYCLIC_NUCLEOTIDE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, ONKEN_UVEAL_MELANOMA_UP, MODULE_157

GO Biological Process (8): cAMP catabolic process (GO:0006198), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), sensory perception of smell (GO:0007608), cellular response to xenobiotic stimulus (GO:0071466), regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106070), negative regulation of cAMP/PKA signal transduction (GO:0141162), regulation of cAMP/PKA signal transduction (GO:0141161)

GO Molecular Function (8): 3’,5’-cyclic-AMP phosphodiesterase activity (GO:0004115), cAMP binding (GO:0030552), metal ion binding (GO:0046872), 3’,5’-cyclic-GMP phosphodiesterase activity (GO:0047555), 3’,5’-cyclic-nucleotide phosphodiesterase activity (GO:0004114), protein binding (GO:0005515), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787)

GO Cellular Component (9): nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), extrinsic component of membrane (GO:0019898), ruffle membrane (GO:0032587), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Opioid Signalling	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
cAMP/PKA signal transduction	2
3’,5’-cyclic-nucleotide phosphodiesterase activity	2
cytoplasm	2
membrane	2
purine ribonucleotide catabolic process	1
cyclic nucleotide catabolic process	1
cAMP metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
sensory perception of chemical stimulus	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
regulation of G protein-coupled receptor signaling pathway	1
regulation of cAMP/PKA signal transduction	1
negative regulation of intracellular signal transduction	1
regulation of intracellular signal transduction	1
cyclic nucleotide binding	1
adenyl ribonucleotide binding	1
anion binding	1
cation binding	1
cyclic-nucleotide phosphodiesterase activity	1
binding	1
phosphoric ester hydrolase activity	1
catalytic activity	1
nuclear lumen	1
cell periphery	1
ruffle	1
cell projection membrane	1
leading edge membrane	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1322 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE4A	DISC1	Q9NRI5	993
PDE4A	AKAP1	Q92667	973
PDE4A	ALDH7A1	P49419	972
PDE4A	ARRB1	P49407	949
PDE4A	ARRB2	P32121	934
PDE4A	AKAP6	Q13023	921
PDE4A	RAPGEF3	O95398	894
PDE4A	PRKACA	P17612	892
PDE4A	PRKACB	P22694	892
PDE4A	PRKACG	P22612	891
PDE4A	RACK1	P25388	841
PDE4A	SAG	P10523	810
PDE4A	ADRB2	P07550	770
PDE4A	SLC25A19	Q9HC21	739
PDE4A	RAPGEF4	Q8WZA2	726

IntAct

26 interactions, top by confidence:

A	B	Type	Score
FKBP6	EEF2K	psi-mi:“MI:0914”(association)	0.530
NHLH2	AP3B1	psi-mi:“MI:0914”(association)	0.530
Dlg4	PDE4A	psi-mi:“MI:0407”(direct interaction)	0.440
PDE4A	HNRNPA2B1	psi-mi:“MI:0915”(physical association)	0.400
PDE4A	METAP2	psi-mi:“MI:0915”(physical association)	0.400
ECE1	PDE4A	psi-mi:“MI:0915”(physical association)	0.370
ITPKB	PDE4A	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AHRR	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
CAMK2B	OGT	psi-mi:“MI:0914”(association)	0.350
CAMK2G	PSMD12	psi-mi:“MI:0914”(association)	0.350
CAMK2D	OGT	psi-mi:“MI:0914”(association)	0.350
CAMK2A	OGT	psi-mi:“MI:0914”(association)	0.350
VEGFB	NPC1	psi-mi:“MI:0914”(association)	0.350
FKBP6	VGF	psi-mi:“MI:0914”(association)	0.350
PDE4D	OXSR1	psi-mi:“MI:0914”(association)	0.350
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350
INSR	UBXN8	psi-mi:“MI:0914”(association)	0.350
INSR	ATOX1	psi-mi:“MI:0914”(association)	0.350
INSR	RIMOC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (28): PDE4A (Affinity Capture-MS), PDE4A (Affinity Capture-MS), PDE4A (Affinity Capture-RNA), PDE4A (Affinity Capture-MS), PDE4A (Affinity Capture-MS), CYB561D2 (Two-hybrid), OSGIN1 (Two-hybrid), PFKFB1 (Two-hybrid), PDE4A (Reconstituted Complex), PDE4A (Proximity Label-MS), PDE4A (Affinity Capture-Western), PDE4A (Affinity Capture-Western), AKAP6 (Affinity Capture-Western), PRKAR2A (Affinity Capture-Western), METAP2 (Affinity Capture-MS)

ESM2 similar proteins: B0K019, B8QB46, O08653, O16844, O43310, O70445, O75381, P13864, P26358, P27815, P46087, P53814, P97434, P97499, Q05469, Q12830, Q1LVK9, Q20548, Q24K09, Q292S8, Q5M775, Q5TKR9, Q60739, Q61712, Q69ZU8, Q6NYJ3, Q6PDI6, Q6WCQ1, Q71M44, Q7ZXG4, Q8BRB7, Q8BZ21, Q8WML3, Q8WYB5, Q921U8, Q92794, Q96KC8, Q96KQ7, Q99933, Q99PI5

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

3 interactions.

A	Effect	B	Mechanism
MAPKAPK2	“down-regulates activity”	PDE4A	phosphorylation
PKA	“up-regulates activity”	PDE4A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Oncogenic MAPK signaling	5	59.1×	8e-07
Signaling by BRAF and RAF1 fusions	5	40.6×	2e-06
Intracellular signaling by second messengers	5	21.8×	2e-05
Diseases of signal transduction by growth factor receptors and second messengers	5	13.5×	1e-04
Dengue Virus-Host Interactions	5	10.9×	3e-04
Cytokine Signaling in Immune system	5	9.7×	5e-04
Cellular responses to stress	5	8.8×	8e-04
Cellular responses to stimuli	5	7.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	68
Likely benign	8
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1410 predictions. Top by Δscore:

Variant	Effect	Δscore
19:10454827:A:AG	acceptor_gain	1.0000
19:10454828:G:GG	acceptor_gain	1.0000
19:10459396:CCA:C	acceptor_loss	1.0000
19:10459397:CAG:C	acceptor_loss	1.0000
19:10459398:A:AG	acceptor_gain	1.0000
19:10459398:A:AT	acceptor_loss	1.0000
19:10459399:G:GG	acceptor_gain	1.0000
19:10459589:TCTCA:T	acceptor_loss	1.0000
19:10459591:TCA:T	acceptor_loss	1.0000
19:10459593:A:AC	acceptor_loss	1.0000
19:10459593:A:AG	acceptor_gain	1.0000
19:10459593:AG:A	acceptor_gain	1.0000
19:10459594:G:GG	acceptor_gain	1.0000
19:10459594:G:GT	acceptor_loss	1.0000
19:10459594:GG:G	acceptor_gain	1.0000
19:10459594:GGA:G	acceptor_gain	1.0000
19:10459594:GGAGC:G	acceptor_gain	1.0000
19:10459755:TAGAT:T	donor_gain	1.0000
19:10459756:AGAT:A	donor_gain	1.0000
19:10459757:GAT:G	donor_gain	1.0000
19:10459757:GATG:G	donor_gain	1.0000
19:10459758:AT:A	donor_gain	1.0000
19:10459758:ATGT:A	donor_loss	1.0000
19:10459759:TGTG:T	donor_loss	1.0000
19:10459760:G:C	donor_loss	1.0000
19:10459760:G:GG	donor_gain	1.0000
19:10459761:T:TC	donor_loss	1.0000
19:10459762:GAG:G	donor_loss	1.0000
19:10459763:AGTG:A	donor_loss	1.0000
19:10459764:G:C	donor_loss	1.0000

AlphaMissense

5778 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:10446333:T:C	F146L	1.000
19:10446334:T:G	F146C	1.000
19:10446335:C:A	F146L	1.000
19:10446335:C:G	F146L	1.000
19:10448943:C:A	P180Q	1.000
19:10448945:T:C	F181L	1.000
19:10448947:T:A	F181L	1.000
19:10448947:T:G	F181L	1.000
19:10448949:C:A	A182D	1.000
19:10449084:T:C	L185P	1.000
19:10449089:A:C	S187R	1.000
19:10449091:C:A	S187R	1.000
19:10449091:C:G	S187R	1.000
19:10449093:T:A	L188H	1.000
19:10449093:T:C	L188P	1.000
19:10449102:T:A	V191D	1.000
19:10449105:G:C	R192P	1.000
19:10450871:T:C	L238P	1.000
19:10450876:T:A	W240R	1.000
19:10450876:T:C	W240R	1.000
19:10450878:G:C	W240C	1.000
19:10450878:G:T	W240C	1.000
19:10450879:T:C	C241R	1.000
19:10450881:T:G	C241W	1.000
19:10450883:T:C	L242P	1.000
19:10450892:T:C	L245P	1.000
19:10450931:C:A	A258D	1.000
19:10454829:T:C	F262L	1.000
19:10454830:T:C	F262S	1.000
19:10454830:T:G	F262C	1.000

dbSNP variants (sampled 300 via entrez): RS1000055077 (19:10469861 C>G,T), RS1000065001 (19:10424864 T>A), RS1000087521 (19:10417407 G>C), RS1000087948 (19:10448622 T>A,C), RS1000102223 (19:10462874 C>T), RS1000126497 (19:10418887 G>C), RS1000222973 (19:10456638 G>A), RS1000236723 (19:10463549 T>C), RS1000254303 (19:10456890 C>G), RS1000328663 (19:10464078 A>T), RS1000345004 (19:10426193 A>G), RS1000367056 (19:10445709 A>C), RS1000418507 (19:10417106 G>A,C), RS1000590045 (19:10458258 T>C), RS1000789896 (19:10452027 G>T)

Disease associations

OMIM: gene MIM:600126 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002740_51	Inflammatory skin disease	3.000000e-14
GCST004131_88	Inflammatory bowel disease	2.000000e-11
GCST004132_111	Crohn’s disease	3.000000e-13
GCST009597_322	Multiple sclerosis	4.000000e-19
GCST011741_22	LDL cholesterol levels in HIV infection	9.000000e-06
GCST011741_6	LDL cholesterol levels in HIV infection	9.000000e-06
GCST90002400_266	Plateletcrit	8.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007985	platelet crit

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), CHEMBL254 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

147 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 366,371 (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
CHEMBL1017	TELMISARTAN	4	27,457
CHEMBL1027	TIAGABINE	4	12,112
CHEMBL1095930	CEFUROXIME AXETIL	4	237
CHEMBL1098319	2-MERCAPTOETHANESULFONIC ACID	4	6,507
CHEMBL1164729	FEBUXOSTAT	4	3,499
CHEMBL1187833	UMECLIDINIUM	4	1,095
CHEMBL119	TRIMETREXATE	4
CHEMBL1200624	ETHYNODIOL DIACETATE	4
CHEMBL1200868	PHENYL AMINOSALICYLATE	4
CHEMBL1200973	ESTRADIOL CYPIONATE	4
CHEMBL1201196	SERTACONAZOLE	4
CHEMBL1237021	LURASIDONE	4
CHEMBL1242	PHENAZOPYRIDINE	4
CHEMBL1262	OXICONAZOLE	4
CHEMBL1289601	LENVATINIB	4
CHEMBL1359	ERTAPENEM	4

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 (15 total), top 15:

Ligand	Action	Affinity	Parameter
rolipram	Inhibition	9.0	pIC50
piclamilast	Inhibition	8.82	pKi
MK-0359	Inhibition	8.8	pIC50
revamilast	Inhibition	8.57	pIC50
YM976	Inhibition	8.3	pIC50
MK-0873	Inhibition	8.22	pIC50
CDP840	Inhibition	8.01	pKi
apremilast	Inhibition	7.85	pIC50
ibudilast	Inhibition	7.27	pIC50
RS-25344	Inhibition	7.2	pIC50
lenrispodun	Inhibition	6.8	pIC50
nerandomilast	Inhibition	6.61	pIC50
Ro20-1724	Inhibition	6.5	pIC50
ensifentrine	Inhibition	5.83	pIC50
6-Hydroxy-5,7-dimethoxyflavone	Inhibition	5.12	pIC50

Binding affinities (BindingDB)

287 measured of 360 human assays (365 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-cyclopentyl-1-[5-[2-(3,5-dichloro-4-pyridinyl)acetyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropane-1-carboxamide	IC50	0.1 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
N-[(2S,3R,4S,6R)-2-[[(1S,2R,5R,6S,7S,8R,9R,11R,13R,14R,15S)-15-[2-[5-[(3,5-dichloro-4-pyridinyl)carbamoyl]-2-(hydroxymethyl)phenoxy]ethylsulfanyl]-2-ethyl-6-hydroxy-9-methoxy-1,5,7,9,11,13-hexamethyl-4,12,16-trioxo-3,17-dioxabicyclo[12.3.0]heptadecan-8-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-methylmorpholine-4-carboxamide	IC50	0.1 nM	US-9738676: Selected macrolides with PDE4-inhibiting activity
1-[5-[2-(3,5-dichloro-4-pyridinyl)acetyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-N-(2,2-dimethylpropyl)cyclopropane-1-carboxamide	IC50	0.2 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
1-[5-[2-(3,5-dichloro-4-pyridinyl)acetyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-N-propan-2-ylcyclopropane-1-carboxamide	IC50	0.2 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
5-chloro-2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-6-(4-oxopentoxy)pyridine-3-carbonitrile	IC50	0.25 nM	US-8716478: Boron-containing small molecules
1-[5-[2-(3,5-dichloro-4-pyridinyl)acetyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-N-propylcyclopropane-1-carboxamide	IC50	0.3 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
CHEMBL315565	IC50	0.398 nM
1-[5-[2-(3,5-dichloro-4-pyridinyl)acetyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-N-(pyridin-4-ylmethyl)cyclopropane-1-carboxamide	IC50	0.4 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
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
N-benzyl-1-[5-[2-(3,5-dichloro-4-pyridinyl)acetyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropane-1-carboxamide	IC50	0.5 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
CHEMBL313982	IC50	0.501 nM
1-[5-[2-(3,5-dichloro-4-pyridinyl)acetyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-N-(pyridin-3-ylmethyl)cyclopropane-1-carboxamide	IC50	0.7 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
5-chloro-6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(4-oxopentoxy)pyridine-3-carbonitrile	IC50	0.8 nM	US-8716478: Boron-containing small molecules
1-[5-[2-(3,5-dichloro-4-pyridinyl)acetyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-N-(pyridin-2-ylmethyl)cyclopropane-1-carboxamide	IC50	1 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(2-propan-2-yloxyethoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile	IC50	1.1 nM	US-8716478: Boron-containing small molecules
5-chloro-2-(2-cyclopropyloxyethoxy)-6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]pyridine-3-carbonitrile	IC50	1.3 nM	US-8716478: Boron-containing small molecules
5-chloro-6-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)oxy]-2-(4-oxopentoxy)pyridine-3-carbonitrile	IC50	1.3 nM	US-8716478: Boron-containing small molecules
triazolopyridazine, 18	IC50	1.5 nM
5-chloro-6-[(7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(4-oxopentoxy)pyridine-3-carbonitrile	IC50	1.7 nM	US-8716478: Boron-containing small molecules
5-chloro-6-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)oxy]-2-(2-propan-2-yloxyethoxy)pyridine-3-carbonitrile	IC50	2 nM	US-8716478: Boron-containing small molecules
1-(2-cyclopropyl-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-(3,5-dichloro-4-pyridinyl)ethanone	IC50	2 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
N-(3,5-dichloro-4-pyridinyl)-7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4’-thiane]-4-carboxamide	IC50	2 nM	US-8980905: Benzodioxole or benzodioxepine heterocyclic compounds as phosphodiesterase inhibitors
6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(4-oxopentoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile	IC50	2.2 nM	US-8716478: Boron-containing small molecules
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
1-[5-[2-(3,5-dichloro-4-pyridinyl)acetyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropane-1-carboxamide	IC50	3 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
1-(2-cyclopropyl-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethanone	IC50	3 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
triazolothiadiazine, 10	IC50	3 nM
triazolothiadiazine, 32	IC50	3.8 nM
2-(3,5-dichloro-4-pyridinyl)-1-[2-[1-(hydroxymethyl)cyclopropyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl]ethanone	IC50	4 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-[6-(difluoromethoxy)spiro[2,4-dihydro-1,5-benzodioxepine-3,4’-oxane]-9-yl]ethanone	IC50	4 nM	US-8980905: Benzodioxole or benzodioxepine heterocyclic compounds as phosphodiesterase inhibitors
2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4’-oxane]-4-yl]ethanone	IC50	5 nM	US-8980905: Benzodioxole or benzodioxepine heterocyclic compounds as phosphodiesterase inhibitors
5-chloro-6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(2-propan-2-yloxyethoxy)pyridine-3-carbonitrile	IC50	5.2 nM	US-9499570: Boron containing small molecules
2-(3,5-dichloro-4-pyridinyl)-1-[6-(difluoromethoxy)spiro[2,4-dihydro-1,5-benzodioxepine-3,3’-oxetane]-9-yl]ethanone	IC50	6 nM	US-8980905: Benzodioxole or benzodioxepine heterocyclic compounds as phosphodiesterase inhibitors
2-(3,5-dichloro-4-pyridinyl)-1-[6-(difluoromethoxy)spiro[2,4-dihydro-1,5-benzodioxepine-3,4’-oxane]-9-yl]ethanone	IC50	6 nM	US-8980905: Benzodioxole or benzodioxepine heterocyclic compounds as phosphodiesterase inhibitors
triazolothiadiazine, 7	IC50	6.1 nM
2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-6-(2-propan-2-yloxyethoxy)pyridine-3,5-dicarbonitrile	IC50	6.5 nM	US-8716478: Boron-containing small molecules
triazolothiadiazine, 42	IC50	6.7 nM
2-(3,5-dichloro-4-pyridinyl)-1-[2-(furan-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl]ethanone	IC50	7 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
2-(3,5-dichloro-4-pyridinyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4’-oxane]-4-yl]ethanone	IC50	7 nM	US-8980905: Benzodioxole or benzodioxepine heterocyclic compounds as phosphodiesterase inhibitors
triazolothiadiazine, 41	IC50	7.1 nM
triazolopyridazine, 17	IC50	7.3 nM
1-[2-[1-[(benzylamino)methyl]cyclopropyl]-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-2-(3,5-dichloro-4-pyridinyl)ethanone	IC50	8 nM	US-8829190: Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
triazolothiadiazine, 37	IC50	8.6 nM
triazolothiadiazine, 31	IC50	9.8 nM
BMCL181297 Compound 5F	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
triazolothiadiazine, 8	IC50	11 nM
triazolothiadiazine, 26	IC50	11 nM
triazolothiadiazine, 36	IC50	11 nM
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

ChEMBL bioactivities

3079 potent at pChembl≥5 of 3522 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
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
10.50	IC50	0.03162	nM	CHEMBL5417689
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
10.22	IC50	0.06	nM	CHEMBL499477
10.15	IC50	0.07	nM	CHEMBL3113978
10.15	IC50	0.07	nM	CHEMBL371037
10.15	IC50	0.07	nM	CHEMBL127944
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	CHEMBL3676245
10.00	IC50	0.1	nM	CHEMBL5081214
10.00	IC50	0.1	nM	CHEMBL5892052
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
9.90	IC50	0.1259	nM	CHEMBL5080391
9.89	IC50	0.13	nM	T-2585.HCL
9.89	IC50	0.13	nM	CHEMBL3113977

PubChem BioAssay actives

2599 with measured affinity, of 5308 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
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3-ethoxy-4-methoxyphenyl)ethyl] 5-[[[(2S)-1-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-3-hydroxy-1-oxo-2-phenylpropan-2-yl]amino]methyl]thiophene-2-carboxylate	2011003: Inhibition of human recombinant PDE4A4 expressed in baculovirus expression system using cAMP as substrate by radiometric assay	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
(4S)-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-2-one	695683: Induction of SQSTM1-dependent intracellular redistribution of GFP-tagged PDE4A4 assessed as maximal accretion of enzyme into foci	ec50	<0.0001	uM
(4S)-4-(4-methoxy-3-propoxyphenyl)pyrrolidin-2-one	695683: Induction of SQSTM1-dependent intracellular redistribution of GFP-tagged PDE4A4 assessed as maximal accretion of enzyme into foci	ec50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(cyclopropylmethoxy)-4-(methanesulfonamido)benzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(methanesulfonamido)-4-methylbenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(cyclopropylmethoxy)-4-methoxybenzoate	1068845: Inhibition of PDE4 activity in human PBMC assessed as inhibition of LPS-induced TNFalpha release after 18 hrs by ELISA	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(dimethylsulfamoyl)-4-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(cyclopropylmethoxy)-4-hydroxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(hydroxymethyl)-4-(methanesulfonamido)benzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 5-(methanesulfonamido)-2-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(methanesulfonamido)-4-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 4-methoxy-3-(methylsulfamoyl)benzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
6-[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)-8-methylquinoline-3-carboxamide	1720022: Inhibition of human PDE4 expressed in Saccharomyces cerevisiae preincubated for 30 mins followed by cAMP substrate addition	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	264615: Inhibition of human GST-PDE4A	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	264615: Inhibition of human GST-PDE4A	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
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	264615: Inhibition of human GST-PDE4A	ic50	0.0001	uM
N-(3,5-dichloro-4-pyridinyl)-1-[3-[(E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(4-methylsulfonylphenyl)ethenyl]phenyl]-4-oxo-1,8-naphthyridine-3-carboxamide	388710: Intrinsic inhibition of GST-fused human PDE4A expressed in SF9 cells	ic50	0.0001	uM
2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-2-pyridinyl]-4-pyridin-3-ylphthalazin-1-one;hydrochloride	159633: Inhibition of guinea pig lung Phosphodiesterase 4	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 4-(methanesulfonamido)-3-methylbenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 4-(cyclopropylmethoxy)-3-(methanesulfonamido)benzoate	1068845: Inhibition of PDE4 activity in human PBMC assessed as inhibition of LPS-induced TNFalpha release after 18 hrs by ELISA	ic50	0.0001	uM
2-methyl-1-[[4-(methylamino)-6-(1,2,4-triazol-1-yl)-1,3,5-triazin-2-yl]amino]cyclohexane-1-carbonitrile	759595: Inhibition of human full length PDE4A4 expressed in baculovirus infected sf21 cells	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(cyclopropylmethoxy)-4-(hydroxymethyl)benzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(cyclopropylmethoxy)-5-(methanesulfonamido)benzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 4-(methanesulfonamido)benzoate	1068845: Inhibition of PDE4 activity in human PBMC assessed as inhibition of LPS-induced TNFalpha release after 18 hrs by ELISA	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(methanesulfonamido)-5-methoxybenzoate	1068845: Inhibition of PDE4 activity in human PBMC assessed as inhibition of LPS-induced TNFalpha release after 18 hrs by ELISA	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] benzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-acetyloxy-4-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3,4-dimethoxybenzoate	1068845: Inhibition of PDE4 activity in human PBMC assessed as inhibition of LPS-induced TNFalpha release after 18 hrs by ELISA	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 4-(methanesulfonamido)-3-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 4-(methanesulfonamido)-2-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
2-(cyclopropylmethoxy)-4-[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethoxy]carbonylbenzoic acid	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 4-methylbenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-hydroxy-4-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-acetamido-4-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 4-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 4-amino-3-(cyclopropylmethoxy)benzoate	1068845: Inhibition of PDE4 activity in human PBMC assessed as inhibition of LPS-induced TNFalpha release after 18 hrs by ELISA	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(cyclopropylmethoxy)-4-(cyclopropylsulfonylamino)benzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	0.0001	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]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
8-(3-nitrophenyl)-6-(pyridin-4-ylmethyl)quinoline	158402: Inhibition of recombinant human PDE4A expressed in Sf9 cells	ic50	0.0001	uM
2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)piperidin-1-yl]-N-hydroxyacetamide	159794: Inhibition of phosphodiesterase 4 (PDE4) prepared from human U937 cells	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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	4
bisphenol A	increases methylation, affects cotreatment, increases expression	2
yessotoxin	decreases expression, increases reaction, affects expression, affects reaction	2
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Doxorubicin	increases expression	2
Estradiol	affects cotreatment, increases expression	2
Formaldehyde	decreases expression, increases expression	2
dicrotophos	increases expression	1
bromacil	affects activity	1
prometone	affects activity	1
propionaldehyde	increases methylation	1
cyanazine	decreases activity	1
nonanal	increases methylation	1
n-hexanal	increases methylation	1
terbacil	affects activity	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases methylation	1
benzo(e)pyrene	increases methylation	1
6-deisopropylatrazine	decreases activity	1
caprylic aldehyde	increases methylation	1
trequinsin	decreases activity	1
pentanal	increases methylation	1
heptanal	increases methylation	1
dimethomorph	decreases activity	1
CGP 52608	affects binding, increases reaction	1
propazine	decreases activity	1
Roflumilast	decreases activity	1

ChEMBL screening assays

581 unique, capped per target: 549 binding, 25 functional, 7 admet

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

6 cell lines: 3 embryonic stem cell, 2 cancer cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5F9	SEES3-1V human PDE4A, clone1	Embryonic stem cell	Male
CVCL_A5G0	SEES3-1V human PDE4A, clone2	Embryonic stem cell	Male
CVCL_A5G1	SEES3-1V human PDE4A, clone3	Embryonic stem cell	Male
CVCL_C0U2	ACTOne cAMP-PDE4A	Spontaneously immortalized cell line	Female
CVCL_TC65	HAP1 PDE4A (-) 1	Cancer cell line	Male
CVCL_TC66	HAP1 PDE4A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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