PDE11A

Summary

PDE11A (phosphodiesterase 11A, HGNC:8773) is a protein-coding gene on chromosome 2q31.2, encoding Dual 3’,5’-cyclic-AMP and -GMP phosphodiesterase 11A (Q9HCR9). Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides cAMP and cGMP.

The 3’,5’-cyclic nucleotides cAMP and cGMP function as second messengers in a wide variety of signal transduction pathways. 3’,5’-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP to the corresponding 5’-monophosphates and provide a mechanism to downregulate cAMP and cGMP signaling. This gene encodes a member of the PDE protein superfamily. Mutations in this gene are a cause of Cushing disease and adrenocortical hyperplasia. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 50940 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pigmented nodular adrenocortical disease, primary, 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 288 total — 8 likely-pathogenic
• Phenotypes (HPO): 83
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_016953

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8773
Approved symbol	PDE11A
Name	phosphodiesterase 11A
Location	2q31.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000128655
Ensembl biotype	protein_coding
OMIM	604961
Entrez	50940

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000286063, ENST00000358450, ENST00000389683, ENST00000409504, ENST00000427127, ENST00000433879, ENST00000436700, ENST00000466790, ENST00000478646, ENST00000488399, ENST00000492761, ENST00000497003

RefSeq mRNA: 4 — MANE Select: NM_016953 NM_001077196, NM_001077197, NM_001077358, NM_016953

CCDS: CCDS33334, CCDS42785, CCDS42786, CCDS46459

Canonical transcript exons

ENST00000286063 — 20 exons

Exon	Start	End
ENSE00001125342	178071526	178072777
ENSE00003703077	177623244	177629562
ENSE00003924704	177663866	177663949
ENSE00003925727	177697332	177697432
ENSE00003927143	177675455	177675518
ENSE00003927472	178014302	178014460
ENSE00003927890	177905098	177905187
ENSE00003929826	177669493	177669567
ENSE00003929861	177701121	177701211
ENSE00003930158	177680826	177680903
ENSE00003930587	177728026	177728172
ENSE00003931262	177875859	177875923
ENSE00003932179	177817858	177817925
ENSE00003933314	177816829	177816921
ENSE00003933833	177769323	177769373
ENSE00003934247	177898058	177898198
ENSE00003934420	177727658	177727765
ENSE00003934994	177840251	177840383
ENSE00003937603	177820220	177820295
ENSE00003937772	177711769	177711878

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 84.22.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5342 / max 77.2253, expressed in 206 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32009	0.4878	186
32006	0.0256	15
32008	0.0084	5
32004	0.0074	4
32005	0.0050	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
deltoid	UBERON:0001476	84.22	silver quality
quadriceps femoris	UBERON:0001377	80.77	silver quality
vastus lateralis	UBERON:0001379	80.56	silver quality
skeletal muscle tissue	UBERON:0001134	76.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.79	gold quality
skeletal muscle organ	UBERON:0014892	74.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	73.97	gold quality
liver	UBERON:0002107	73.85	gold quality
gastrocnemius	UBERON:0001388	73.53	gold quality
muscle of leg	UBERON:0001383	73.29	gold quality
muscle tissue	UBERON:0002385	73.24	gold quality
prostate gland	UBERON:0002367	71.81	gold quality
biceps brachii	UBERON:0001507	71.70	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	70.76	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.55	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	70.10	gold quality
right lobe of liver	UBERON:0001114	69.89	gold quality
tibialis anterior	UBERON:0001385	69.48	silver quality
hindlimb stylopod muscle	UBERON:0004252	69.08	gold quality
tibia	UBERON:0000979	69.05	gold quality
spinal cord	UBERON:0002240	68.74	gold quality
medial globus pallidus	UBERON:0002477	68.69	silver quality
corpus callosum	UBERON:0002336	66.42	gold quality
left testis	UBERON:0004533	65.13	gold quality
testis	UBERON:0000473	65.12	gold quality
globus pallidus	UBERON:0001875	64.57	silver quality
substantia nigra	UBERON:0002038	63.73	gold quality
adrenal tissue	UBERON:0018303	63.72	gold quality
right testis	UBERON:0004534	63.51	gold quality
smooth muscle tissue	UBERON:0001135	63.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

201 targeting PDE11A, 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-4668-3P	100.00	68.74	2635
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3148	99.97	75.06	6478

Literature-anchored findings (GeneRIF, showing 19)

• we detected protein corresponding to PDE11A4, in human prostate, pituitary, heart and liver (PMID:15800651)
• PDE11A genetic defects may be associated with adrenal pathology in a wider than previously suspected and is associated with adrenal hyperplasia and adenomas. (PMID:17178847)
• Variants in PDE11A are not associated with citalopram response in patient with depression. (PMID:18043711)
• N-terminal modifications strongly affect cGMP regulation of hPDE11A4 (PMID:18312413)
• PDE11A is expressed widely in adrenal cortex. Its expression appears to be increased in PPNAD but varies widely among other adrenocortical tumors. (PMID:18491255)
• PDE11A sequence defects predispose to a variety of lesions (beyond micronodular adrenocortical hyperplasia). (PMID:18559625)
• PDE11A, is unlikely to play an important role in antidepressant outcome in this sample (PMID:19214142)
• PDE11A-inactivating sequence variants may modify the risk of familial and bilateral testicular germ cell tumors. (PMID:19549888)
• Immunohistochemistry revealed PDE11A expression higher in somatotropinomas than in normal somatotrophs, without significant difference between tumors with or without PDE11A variants. (PMID:19671705)
• Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity. (PMID:19689430)
• Our data suggest that, like in the adrenal cortex and the testicular germ cells, PDE11A-inactivating genetic alterations may play a role in susceptibility to prostate cancer (PMID:20881257)
• PDE11A SNP assocaited with allergic asthma. (PMID:20920776)
• We demonstrate, in a large cohort of Carney Complex patients, a high frequency of PDE11A variants, suggesting that PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation. (PMID:21047926)
• found in single nerve trunks in the clitoral stroma (PMID:21697861)
• PDE11A genetic variants may increase predisposition to ACTH-independent macronodular adrenal hyperplasia. (PMID:22996146)
• Testicular germ cell tumors had 55 PDE11A variants: 20 missense (10 new, 9 in transcript variant 4, 1 in transcript variant 3), 4 splice-site, 2 nonsense, 7 synonymous, and 22 intronic. p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R were only in cases. (PMID:26459559)
• One percent of the Swedish population carries a PDE11A loss-of-function mutation which is associated with elevated BP, abdominal obesity, and risk of ischemic stroke. (PMID:26820475)
• PDE11A gene polymorphism in testicular cancer: sperm parameters and hormonal profile. (PMID:33661511)
• Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer’s disease. (PMID:33835157)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	pde11al	ENSDARG00000006151
danio_rerio	si:dkey-219c10.4	ENSDARG00000075929
mus_musculus	Pde11a	ENSMUSG00000075270
rattus_norvegicus	Cyct	ENSRNOG00000024457
drosophila_melanogaster	Pde11	FBGN0085370
drosophila_melanogaster	Pde9	FBGN0259171
drosophila_melanogaster	Pde8	FBGN0266377
caenorhabditis_elegans		WBGENE00008443
caenorhabditis_elegans	pde-6	WBGENE00022389

Paralogs (20): PDE4A (ENSG00000065989), PDE8A (ENSG00000073417), PDE6C (ENSG00000095464), PDE4C (ENSG00000105650), PDE10A (ENSG00000112541), PDE8B (ENSG00000113231), PDE4D (ENSG00000113448), PDE1A (ENSG00000115252), PDE1B (ENSG00000123360), 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

Dual 3’,5’-cyclic-AMP and -GMP phosphodiesterase 11A — Q9HCR9 (reviewed: Q9HCR9)

Alternative names: cAMP and cGMP phosphodiesterase 11A

All UniProt accessions (4): Q9HCR9, F8WDQ4, H0Y6P9, H7C4D0

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides cAMP and cGMP. Catalyzes the hydrolysis of both cAMP and cGMP to 5’-AMP and 5’-GMP, respectively.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Isoform 1 is present in prostate, pituitary, heart and liver. It is however not present in testis nor in penis, suggesting that weak inhibition by Tadalafil (Cialis) is not relevant (at protein level). Isoform 2 may be expressed in testis. Isoform 4 is expressed in adrenal cortex.

Disease relevance. Primary pigmented nodular adrenocortical disease 2 (PPNAD2) [MIM:610475] A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by 3-isobutyl-1-methylxanthine (IBMX), zaprinast and dipyridamole. cGMP acts as an allosteric activator. Weakly inhibited by Sildenafil (Viagra) and Tadalafil (Cialis); however, the fact that the protein is probably absent from testis, suggests that it is not biologically relevant and is not related with erectile dysfunction.

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. The tandem GAF domains bind cGMP, and regulate enzyme activity. The binding of cGMP stimulates enzyme activity.

Similarity. Belongs to the cyclic nucleotide phosphodiesterase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9HCR9-1	1, PDE11A4	yes
Q9HCR9-2	2, PDE11A3
Q9HCR9-3	3, PDE11A2
Q9HCR9-4	4, PDE11A1

RefSeq proteins (4): NP_001070664, NP_001070665, NP_001070826, NP_058649* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002073	PDEase_catalytic_dom	Domain
IPR003018	GAF	Domain
IPR003607	HD/PDEase_dom	Domain
IPR023088	PDEase	Family
IPR023174	PDEase_CS	Conserved_site
IPR029016	GAF-like_dom_sf	Homologous_superfamily
IPR036971	PDEase_catalytic_dom_sf	Homologous_superfamily

Pfam: PF00233, PF01590

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)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3’,5’-CAMP	0.0001–7	41
3’,5’-CGMP	—	23
CAMP	0.0002–1.6	15
CGMP	0.0002–1	12
2’,3’-CAMP	0.0038–0.0052	2
5’-AMP	0.0014–0.0016	2
5’-ATP	0.0033–0.0125	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), 2 shown:

• 3’,5’-cyclic GMP + H2O = GMP + H(+) (RHEA:16957)
• 3’,5’-cyclic AMP + H2O = AMP + H(+) (RHEA:25277)

UniProt features (24 total): binding site 6, splice variant 4, domain 3, modified residue 3, sequence variant 2, sequence conflict 2, chain 1, mutagenesis site 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCR9-F1	79.12	0.47

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): 664 (proton donor)

Ligand- & substrate-binding residues (6): 705; 816; 424; 668; 704; 705

Post-translational modifications (3): 162, 163, 239

Mutagenesis-validated functional residues (1):

Position	Phenotype
355	induces a decrease in enzyme activity due to the inability of cgmp to bind and stimulate enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-418457	cGMP effects
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 329 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, AREB6_03, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, KEGG_PURINE_METABOLISM, GOMF_CYCLIC_NUCLEOTIDE_PHOSPHODIESTERASE_ACTIVITY, GOMF_PHOSPHORIC_DIESTER_HYDROLASE_ACTIVITY, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS, GOMF_PHOSPHORIC_ESTER_HYDROLASE_ACTIVITY, GOMF_CYCLIC_NUCLEOTIDE_BINDING, GOMF_CGMP_BINDING, MIKKELSEN_MEF_ICP_WITH_H3K27ME3, MIKKELSEN_IPS_ICP_WITH_H3K4ME3_AND_H327ME3, MIKKELSEN_ES_ICP_WITH_H3K4ME3_AND_H3K27ME3, GOBP_RECEPTOR_GUANYLYL_CYCLASE_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_RECEPTOR_GUANYLYL_CYCLASE_SIGNALING_PATHWAY

GO Biological Process (3): signal transduction (GO:0007165), negative regulation of receptor guanylyl cyclase signaling pathway (GO:0010754), negative regulation of cAMP/PKA signal transduction (GO:0141162)

GO Molecular Function (11): cyclic-nucleotide phosphodiesterase activity (GO:0004112), 3’,5’-cyclic-nucleotide phosphodiesterase activity (GO:0004114), 3’,5’-cyclic-AMP phosphodiesterase activity (GO:0004115), 3’,5’-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity (GO:0004118), cGMP binding (GO:0030553), metal ion binding (GO:0046872), 3’,5’-cyclic-GMP phosphodiesterase activity (GO:0047555), catalytic activity (GO:0003824), protein binding (GO:0005515), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Nitric oxide stimulates guanylate cyclase	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
3’,5’-cyclic-nucleotide phosphodiesterase activity	3
cellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor guanylyl cyclase signaling pathway	1
negative regulation of signal transduction	1
cAMP/PKA signal transduction	1
regulation of cAMP/PKA signal transduction	1
negative regulation of intracellular signal transduction	1
phosphoric diester hydrolase activity	1
cyclic-nucleotide phosphodiesterase activity	1
cyclic nucleotide binding	1
guanyl ribonucleotide binding	1
anion binding	1
cation binding	1
molecular_function	1
binding	1
phosphoric ester hydrolase activity	1
catalytic activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

776 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE11A	PRKAR1A	P10644	917
PDE11A	ALDH7A1	P49419	830
PDE11A	ARMC5	Q96C12	724
PDE11A	PRKACA	P17612	640
PDE11A	PRKACB	P22694	611
PDE11A	GNAS	Q5JWF2	590
PDE11A	PRKACG	P22612	581
PDE11A	CREB1	P16220	560
PDE11A	PDE5A	O76074	545
PDE11A	PDE3A	Q14432	534
PDE11A	PDE3B	Q13370	514
PDE11A	MC2R	Q01718	489
PDE11A	GPR101	Q96P66	479
PDE11A	POMC	P01189	471
PDE11A	RELA	Q04206	457

IntAct

0 interactions, top by confidence:

BioGRID (2): PDE11A (Negative Genetic), PDE11A (Affinity Capture-MS)

ESM2 similar proteins: A0A0B7P9G0, A0A131MCZ8, A2PYH4, A3QM97, B4JXX2, B4QZU1, E1BPX4, G5EBX9, O00835, O13768, O14072, O74431, P32639, P36583, P36775, P38329, P39986, P40527, P47047, P53273, P53914, P87115, P91119, P92006, Q07093, Q09769, Q12296, Q21029, Q3UYK3, Q55EJ3, Q67XQ0, Q6BMW3, Q6CNR9, Q6FPE6, Q6P4Q7, Q6ZT07, Q84K47, Q8RY60, Q9BMK9, Q9FKF2

Diamond homologs: B3LVW5, B3P3K2, B4G4E5, B4HEM4, B4JXX2, B4K9L4, B4LVU6, B4NAL6, B4PSS5, B4QZU1, B7YZV4, H2QL32, O00408, O54735, O70628, O76074, O76083, O77746, O89084, P0C1Q2, P11541, P14099, P14100, P14644, P14646, P16499, P16586, P23439, P23440, P27664, P27815, P30645, P33726, P35913, P51160, P52731, P54748, P54750, P91119, Q01061

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
tadalafil	“down-regulates activity”	PDE11A	“chemical inhibition”
PKA	“up-regulates activity”	PDE11A	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	8
Uncertain significance	186
Likely benign	29
Benign	30

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1324867	NM_016953.4(PDE11A):c.1270_1280del (p.Ser424fs)	Likely pathogenic
1324868	NM_016953.4(PDE11A):c.1585C>T (p.Gln529Ter)	Likely pathogenic
1333997	NM_016953.4(PDE11A):c.1913_1915delinsG (p.Gln638fs)	Likely pathogenic
2432520	NM_016953.4(PDE11A):c.1149T>A (p.Tyr383Ter)	Likely pathogenic
3780107	NM_016953.4(PDE11A):c.2056C>T (p.Gln686Ter)	Likely pathogenic
4081584	NM_016953.4(PDE11A):c.1243C>T (p.Gln415Ter)	Likely pathogenic
422034	NM_016953.4(PDE11A):c.1936-2A>T	Likely pathogenic
503786	NM_016953.4(PDE11A):c.460_461del (p.Arg154fs)	Likely pathogenic

SpliceAI

4866 predictions. Top by Δscore:

Variant	Effect	Δscore
2:177669491:A:AC	donor_gain	1.0000
2:177669492:C:CC	donor_gain	1.0000
2:177680820:TCTTA:T	donor_loss	1.0000
2:177680821:CTTA:C	donor_loss	1.0000
2:177680822:TTA:T	donor_loss	1.0000
2:177680823:TACCG:T	donor_loss	1.0000
2:177680824:A:AC	donor_gain	1.0000
2:177680824:A:AT	donor_loss	1.0000
2:177680825:C:CC	donor_gain	1.0000
2:177680825:C:CT	donor_loss	1.0000
2:177680904:C:CC	acceptor_gain	1.0000
2:177680905:T:C	acceptor_loss	1.0000
2:177680916:C:CT	acceptor_gain	1.0000
2:177680917:A:T	acceptor_gain	1.0000
2:177680919:A:AC	acceptor_gain	1.0000
2:177680919:A:C	acceptor_gain	1.0000
2:177697330:A:AC	donor_gain	1.0000
2:177697331:C:CC	donor_gain	1.0000
2:177701124:A:AC	donor_gain	1.0000
2:177701125:C:CC	donor_gain	1.0000
2:177711765:TTA:T	donor_loss	1.0000
2:177711766:TACT:T	donor_loss	1.0000
2:177711767:A:AC	donor_gain	1.0000
2:177711767:ACT:A	donor_loss	1.0000
2:177711768:C:CG	donor_gain	1.0000
2:177711768:CT:C	donor_gain	1.0000
2:177711768:CTT:C	donor_gain	1.0000
2:177711768:CTTA:C	donor_gain	1.0000
2:177711768:CTTAG:C	donor_gain	1.0000
2:177711771:AG:A	donor_gain	1.0000

AlphaMissense

6182 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:177669541:G:C	F838L	1.000
2:177669541:G:T	F838L	1.000
2:177669543:A:G	F838L	1.000
2:177675495:T:G	D816A	1.000
2:177697350:T:C	D776G	1.000
2:177697362:A:T	I772K	1.000
2:177701131:A:G	L745P	1.000
2:177701144:C:G	A741P	1.000
2:177701156:G:C	H737D	1.000
2:177701157:G:C	H736Q	1.000
2:177701157:G:T	H736Q	1.000
2:177701159:G:C	H736D	1.000
2:177701163:C:A	E734D	1.000
2:177701163:C:G	E734D	1.000
2:177701164:T:A	E734V	1.000
2:177701188:A:G	L726P	1.000
2:177711777:G:C	F715L	1.000
2:177711777:G:T	F715L	1.000
2:177711779:A:G	F715L	1.000
2:177711783:A:C	N713K	1.000
2:177711783:A:T	N713K	1.000
2:177711786:G:C	N712K	1.000
2:177711786:G:T	N712K	1.000
2:177711793:C:T	G710E	1.000
2:177711802:T:A	D707V	1.000
2:177711808:T:A	D705V	1.000
2:177711808:T:G	D705A	1.000
2:177727705:A:G	W666R	1.000
2:177727705:A:T	W666R	1.000
2:177727711:G:C	H664D	1.000

dbSNP variants (sampled 300 via entrez): RS1000001250 (2:177809896 C>T), RS1000006609 (2:178028430 T>A), RS1000019002 (2:177856741 T>A), RS1000019834 (2:177650161 G>C,T), RS1000024167 (2:177849534 C>T), RS1000025147 (2:178007984 G>A,C,T), RS1000026503 (2:177766152 G>A,T), RS1000032287 (2:177628363 A>C), RS1000033322 (2:178035113 A>C), RS1000034716 (2:177720545 G>C), RS1000034986 (2:177782543 C>T), RS1000045198 (2:177693571 A>G), RS1000045686 (2:177789683 A>C), RS1000059475 (2:177982213 G>C), RS1000061689 (2:177907032 G>A)

Disease associations

OMIM: gene MIM:604961 | disease phenotypes: MIM:610475, MIM:615993

GenCC curated gene-disease

Disease	Classification	Inheritance
pigmented nodular adrenocortical disease, primary, 2	Strong	Autosomal dominant
primary pigmented nodular adrenocortical disease	Supportive	Autosomal dominant

Mondo (3): pigmented nodular adrenocortical disease, primary, 2 (MONDO:0012505), Bardet-Biedl syndrome 16 (MONDO:0014444), primary pigmented nodular adrenocortical disease (MONDO:0015999)

Orphanet (2): OBSOLETE: Primary pigmented nodular adrenocortical disease (Orphanet:189439), Bardet-Biedl syndrome (Orphanet:110)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000053	Macroorchidism
HP:0000098	Tall stature
HP:0000138	Ovarian cyst
HP:0000199	Tongue nodules
HP:0000311	Round face
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000712	Emotional lability
HP:0000713	Agitation
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000771	Gynecomastia
HP:0000798	Oligozoospermia
HP:0000822	Hypertension
HP:0000826	Precocious puberty
HP:0000845	Elevated circulating growth hormone concentration
HP:0000866	Euthyroid multinodular goiter
HP:0000870	Increased circulating prolactin concentration
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000963	Thin skin
HP:0000978	Bruising susceptibility
HP:0001003	Multiple lentigines
HP:0001007	Hirsutism
HP:0001065	Striae distensae
HP:0001074	Atypical nevi in non-sun exposed areas
HP:0001268	Mental deterioration
HP:0001297	Stroke

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000817_189	Height	3.000000e-08
GCST001969_31	Heart rate	3.000000e-07
GCST003997_30	Myopia	1.000000e-20
GCST004049_6	Cough in response to angiotensin-converting enzyme inhibitor drugs	6.000000e-07
GCST005875_1	Diastolic blood pressure	1.000000e-06
GCST006291_114	Spherical equivalent or myopia (age of diagnosis)	2.000000e-16
GCST006628_8	Systolic blood pressure	5.000000e-09
GCST007637_24	Diffusing capacity of carbon monoxide	2.000000e-09
GCST008163_85	Height	6.000000e-06
GCST009962_8	High myopia	2.000000e-08
GCST010002_405	Refractive error	1.000000e-70
GCST012163_6	Adiponectin levels x Mediterranean diet adherence interaction	6.000000e-06
GCST012227_1235	Hip circumference adjusted for BMI	3.000000e-10
GCST012403_136	High myopia	8.000000e-06
GCST012489_26	Heel bone mineral density x serum urate levels interaction	1.000000e-08
GCST012489_55	Heel bone mineral density x serum urate levels interaction	1.000000e-09
GCST90000025_830	Appendicular lean mass	8.000000e-14

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0006336	diastolic blood pressure
EFO:0004847	age at onset
EFO:0006335	systolic blood pressure
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0004502	adiponectin measurement
EFO:0008111	diet measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566472	Pigmented Nodular Adrenocortical Disease, Primary, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2717 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 154,241 (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
CHEMBL1520	VARDENAFIL	4	21,078
CHEMBL192	SILDENAFIL	4	41,819
CHEMBL779	TADALAFIL	4	23,417
CHEMBL932	DIPYRIDAMOLE	4	51,743
CHEMBL28079	ZAPRINAST	2	16,158
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
tadalafil	Inhibition	6.52	pIC50
BC11-38	Inhibition	6.5	pIC50

Binding affinities (BindingDB)

15 measured of 54 human assays (54 total across all organisms); most potent 15 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4,5-dimethyl-8-phenyl-12-propylsulfanyl-3-thia-1,8,10,11-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),4,9,11-tetraen-7-one	IC50	50 nM	US-9173884: Inhibitors of phosphodiesterase 11 (PDE11)
2-benzamido-N-(1-methylbenzimidazol-2-yl)benzamide	IC50	150 nM	US-9173884: Inhibitors of phosphodiesterase 11 (PDE11)
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
N-(2-methylphenyl)-7-(4-methylphenyl)-5-phenylpyrrolo[2,3-d]pyrimidin-4-amine	IC50	500 nM	US-9173884: Inhibitors of phosphodiesterase 11 (PDE11)
7-(4-methoxyphenyl)-N-(2-methylphenyl)-5-phenylpyrrolo[2,3-d]pyrimidin-4-amine	IC50	1000 nM	US-9173884: Inhibitors of phosphodiesterase 11 (PDE11)
SILDENAFIL CITRATE	IC50	1500 nM
N-benzyl-7-(4-fluorophenyl)-5-phenylpyrrolo[2,3-d]pyrimidin-4-amine	IC50	1500 nM	US-9173884: Inhibitors of phosphodiesterase 11 (PDE11)
8-ethoxy-3-phenyl-[1,3,5]triazino[2,1-b][1,3]benzothiazole-2,4-dione	IC50	2000 nM	US-9173884: Inhibitors of phosphodiesterase 11 (PDE11)
3-(3-chlorophenyl)-8-methoxy-[1,3,5]triazino[2,1-b][1,3]benzothiazole-2,4-dione	IC50	2000 nM	US-9173884: Inhibitors of phosphodiesterase 11 (PDE11)
7-(4-chlorophenyl)-N-(2-methylphenyl)-5-phenylpyrrolo[2,3-d]pyrimidin-4-amine	IC50	2000 nM	US-9173884: Inhibitors of phosphodiesterase 11 (PDE11)
3-benzyl-8-methoxy-[1,3,5]triazino[2,1-b][1,3]benzothiazole-2,4-dione	IC50	2000 nM	US-9173884: Inhibitors of phosphodiesterase 11 (PDE11)
(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

259 potent at pChembl≥5 of 279 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.15	IC50	0.7	nM	CHEMBL5437525
8.85	IC50	1.4	nM	CHEMBL282515
8.70	IC50	2.01	nM	CHEMBL284070
8.66	IC50	2.2	nM	CHEMBL282515
8.62	IC50	2.4	nM	CHEMBL33518
8.57	IC50	2.7	nM	CHEMBL4217054
8.46	IC50	3.5	nM	CHEMBL418594
8.40	IC50	4	nM	CHEMBL4292389
8.38	IC50	4.2	nM	CHEMBL33121
8.37	IC50	4.3	nM	CHEMBL285737
8.33	IC50	4.7	nM	CHEMBL286309
8.33	IC50	4.7	nM	CHEMBL33627
8.29	IC50	5.1	nM	CHEMBL4217579
8.26	IC50	5.5	nM	CHEMBL32255
8.19	IC50	6.5	nM	CHEMBL34744
8.17	IC50	6.7	nM	CHEMBL34276
8.00	IC50	10	nM	TADALAFIL
7.96	IC50	11	nM	CHEMBL1650866
7.93	IC50	11.8	nM	CHEMBL284560
7.92	IC50	12	nM	CHEMBL5432407
7.82	IC50	15	nM	CHEMBL6163944
7.82	IC50	15	nM	CHEMBL6173500
7.82	IC50	15	nM	CHEMBL6142827
7.80	IC50	16	nM	CHEMBL5408783
7.70	IC50	20	nM	TADALAFIL
7.66	IC50	22.1	nM	TADALAFIL
7.66	IC50	22	nM	CHEMBL34802
7.60	IC50	25	nM	TADALAFIL
7.57	IC50	27	nM	CHEMBL6170834
7.52	IC50	30	nM	CHEMBL6176945
7.51	IC50	31	nM	CHEMBL33381
7.48	IC50	33	nM	TADALAFIL
7.47	IC50	34	nM	CHEMBL6175036
7.46	IC50	34.7	nM	CHEMBL4128481
7.44	IC50	36	nM	CHEMBL6168839
7.43	IC50	37	nM	TADALAFIL
7.41	IC50	39	nM	CHEMBL4218772
7.41	IC50	39	nM	CHEMBL6170922
7.41	IC50	39	nM	CHEMBL34169
7.39	IC50	41	nM	CHEMBL6171500
7.38	IC50	42	nM	CHEMBL6174438
7.38	IC50	42	nM	CHEMBL6175530
7.37	IC50	43	nM	CHEMBL33944
7.36	IC50	44	nM	CHEMBL6169545
7.36	IC50	44	nM	CHEMBL284560
7.35	IC50	45	nM	CHEMBL6169979
7.33	IC50	47	nM	TADALAFIL
7.33	IC50	47	nM	CHEMBL6166825
7.32	IC50	48	nM	CHEMBL284627
7.32	IC50	48	nM	CHEMBL33147

PubChem BioAssay actives

209 with measured affinity, of 463 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
2-anilino-7-morpholin-4-yl-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4-one	2037299: Inhibition of PDE11A (unknown origin)	ic50	0.0007	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-[2-(1-methylimidazol-2-yl)ethyl]pyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0014	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-(2-pyridin-2-ylethyl)pyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0020	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-(2-pyridin-3-ylethyl)pyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0024	uM
(3S)-3-(5-ethylthiophen-2-yl)-2-(5-pyridin-2-ylpyrimidin-2-yl)-3,4-dihydro-1H-pyrrolo[3,4-b]quinolin-9-one	1383533: Inhibition of N-terminal GST-tagged full length recombinant human PDE11A expressed in Baculovirus infected Sf9 insect cells using FAM-cAMP as substrate after 1 hr by fluorescence polarization assay	ic50	0.0027	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-[2-(1H-imidazol-2-yl)ethyl]pyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0035	uM
(10S,15S)-13-ethyl-10-(5-methylfuran-2-yl)-8,11,13-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(9),2,4,6-tetraene-12,14-dione	1421860: Inhibition of full length recombinant human N-terminal GST-tagged PDE11A4 expressed in baculovirus infected sf9 cells using FAM-cyclic-3’,5-AMP as substrate after 1 hr by fluorescence polarization assay	ic50	0.0040	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-(2-pyrazin-2-ylethyl)pyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0042	uM
3-[(3R)-3-[(2R,8R)-2-(1,3-benzodioxol-5-yl)-4,7-dioxo-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraen-6-yl]pyrrolidin-1-yl]-N-ethylpropanamide	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0043	uM
(2R,8R)-6-[(3R)-1-[3-(azetidin-1-yl)-3-oxopropyl]pyrrolidin-3-yl]-2-(1,3-benzodioxol-5-yl)-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0047	uM
3-[(3R)-3-[(2R,8R)-2-(1,3-benzodioxol-5-yl)-4,7-dioxo-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraen-6-yl]pyrrolidin-1-yl]-N,N-dimethylpropanamide	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0047	uM
(3S)-3-(5-ethylfuran-2-yl)-2-(5-pyridin-2-ylpyrimidin-2-yl)-3,4-dihydro-1H-pyrrolo[3,4-b]quinolin-9-one	1383533: Inhibition of N-terminal GST-tagged full length recombinant human PDE11A expressed in Baculovirus infected Sf9 insect cells using FAM-cAMP as substrate after 1 hr by fluorescence polarization assay	ic50	0.0051	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-benzylpyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0055	uM
(2R,8R)-6-[(3R)-1-benzylpyrrolidin-3-yl]-2-(4-methylphenyl)-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0065	uM
(2R,8R)-6-[(3R)-1-benzylpyrrolidin-3-yl]-2-(4-methoxyphenyl)-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0067	uM
Tadalafil	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	0.0100	uM
(2R,8R)-2-(2,4-dichlorophenyl)-6-ethyl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	566807: Inhibition of human recombinant PDE11A-mediated hydrolysis of cGMP after 30 mins by fluorescence polarization assay	ic50	0.0110	uM
(2R,8R)-6-[(3R)-1-benzylpyrrolidin-3-yl]-2-(3-methoxyphenyl)-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0118	uM
3-(difluoromethyl)-N,N-diethyl-6-(2-methylpyrazol-3-yl)-1-phenylpyrazolo[5,4-b]pyridine-4-carboxamide	2037307: Inhibition of N-terminal GST-tagged human recombinant PDE11A4 (1 to 943 residues) expressed in Sf9 insect cells using cAMP as substrate	ic50	0.0120	uM
3-(difluoromethyl)-6-(2-methylpyrazol-3-yl)-N,N-bis(1,1,2,2,2-pentadeuterioethyl)-1-phenylpyrazolo[5,4-b]pyridine-4-carboxamide	2037307: Inhibition of N-terminal GST-tagged human recombinant PDE11A4 (1 to 943 residues) expressed in Sf9 insect cells using cAMP as substrate	ic50	0.0160	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-(3-methoxypropyl)pyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0220	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-pentylpyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0310	uM
7,8-dimethoxy-N-[(2S)-1-(5-methyl-1H-pyrazol-3-yl)propan-2-yl]quinazolin-4-amine	1495741: Inhibition of full length recombinant human PDE11A4 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0347	uM
3-(1,3-benzodioxol-5-ylmethyl)-8-hydroxy-6-(2-methoxyethylamino)-1-(1,3-thiazol-2-yl)-2H-chromeno[2,3-c]pyrrol-9-one	1386227: Inhibition of PDE11A catalytic domain (588 to 911 residues) (unknown origin) expressed in Escherichia coli BL21 using 3H-cAMP as substrate after 15 mins by liquid scintillation counting	ic50	0.0390	uM
(2R,8R)-6-[(3R)-1-benzylpyrrolidin-3-yl]-2-(6-oxo-1H-pyridin-3-yl)-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0390	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-(2-cyclopropylethyl)pyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0430	uM
3-[(3R)-3-[(2R,8R)-2-(1,3-benzodioxol-5-yl)-4,7-dioxo-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraen-6-yl]pyrrolidin-1-yl]propanamide	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0480	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-[3-(dimethylamino)-2-oxopropyl]pyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0480	uM
1-(2-chlorophenyl)-N,N-diethyl-3-methyl-6-(2-methylpyrazol-3-yl)pyrazolo[5,4-b]pyridine-4-carboxamide	2037307: Inhibition of N-terminal GST-tagged human recombinant PDE11A4 (1 to 943 residues) expressed in Sf9 insect cells using cAMP as substrate	ic50	0.0510	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[2-(dimethylamino)ethyl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0530	uM
N,N-diethyl-3-methyl-6-(2-methylpyrazol-3-yl)-1-phenylpyrazolo[5,4-b]pyridine-4-carboxamide	2037307: Inhibition of N-terminal GST-tagged human recombinant PDE11A4 (1 to 943 residues) expressed in Sf9 insect cells using cAMP as substrate	ic50	0.0530	uM
N,N-diethyl-6-(2-ethylpyrazol-3-yl)-3-methyl-1-phenylpyrazolo[5,4-b]pyridine-4-carboxamide	2037307: Inhibition of N-terminal GST-tagged human recombinant PDE11A4 (1 to 943 residues) expressed in Sf9 insect cells using cAMP as substrate	ic50	0.0610	uM
N,N-diethyl-6-(2-ethylpyrazol-3-yl)-1-(2-fluorophenyl)-3-methylpyrazolo[5,4-b]pyridine-4-carboxamide	2037307: Inhibition of N-terminal GST-tagged human recombinant PDE11A4 (1 to 943 residues) expressed in Sf9 insect cells using cAMP as substrate	ic50	0.0620	uM
3-[(4-hydroxycyclohexyl)amino]-7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446797: Inhibition of PDE11	ic50	0.0641	uM
N-(12-methoxy-5-methyl-3-propyl-2,4,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaen-7-yl)methanesulfonamide	484818: Inhibition of PDE11A	ic50	0.0686	uM
(2R,8R)-6-[(3R)-1-benzylpyrrolidin-3-yl]-2-(4-methoxy-3-methylphenyl)-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0710	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6,8-dimethyl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	1395055: Inhibition of recombinant human PDE11A4 expressed in Sf9 insect cells using [3H]cGMP or [3H]cAMP as substrate after 10 mins by scintillation counting analysis	ic50	0.0730	uM
N,N-diethyl-6-(2-methylpyrazol-3-yl)-1-phenyl-3-(trifluoromethyl)pyrazolo[5,4-b]pyridine-4-carboxamide	2037307: Inhibition of N-terminal GST-tagged human recombinant PDE11A4 (1 to 943 residues) expressed in Sf9 insect cells using cAMP as substrate	ic50	0.0810	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3S)-1-benzylpyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.0850	uM
N,N-diethyl-1-(4-fluorophenyl)-3-methyl-6-(2-methylpyrazol-3-yl)pyrazolo[5,4-b]pyridine-4-carboxamide	2037307: Inhibition of N-terminal GST-tagged human recombinant PDE11A4 (1 to 943 residues) expressed in Sf9 insect cells using cAMP as substrate	ic50	0.0910	uM
(10S,15R)-13-ethyl-10-(5-ethylfuran-2-yl)-8,11,13-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(9),2,4,6-tetraene-12,14-dione	1421860: Inhibition of full length recombinant human N-terminal GST-tagged PDE11A4 expressed in baculovirus infected sf9 cells using FAM-cyclic-3’,5-AMP as substrate after 1 hr by fluorescence polarization assay	ic50	0.0990	uM
7-(4-fluorophenyl)-N-(2-methylphenyl)-5-phenylpyrrolo[2,3-d]pyrimidin-4-amine	1799706: In Vitro Enzyme Assay from Article 10.1016/j.chembiol.2011.12.010: “Identification of biologically active PDE11-selective inhibitors using a yeast-based high-throughput screen.”	ic50	0.1100	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-but-3-enylpyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	159035: Inhibitory activity against phosphodiesterase 11 (PDE11) obtained from recombinant Sf9 expression	ic50	0.1180	uM
(2S,8R)-2-(5-ethylfuran-2-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	1421860: Inhibition of full length recombinant human N-terminal GST-tagged PDE11A4 expressed in baculovirus infected sf9 cells using FAM-cyclic-3’,5-AMP as substrate after 1 hr by fluorescence polarization assay	ic50	0.1190	uM
Vardenafil	241009: Inhibition of human phosphodiesterase 11	ic50	0.1300	uM
8-[5-(aminomethyl)-2-[8-methoxy-2-(trifluoromethyl)quinolin-5-yl]-1,3-oxazole-4-carbonyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	309106: Inhibition of PDE11	ic50	0.1300	uM
1’,2’-dibenzyl-5’-ethylspiro[1,2-dihydroindene-3,7’-8H-imidazo[2,1-b]purine]-4’-one	598790: Inhibition of PDE11	ic50	0.1400	uM
2-[5-(3,4-dimethoxyphenyl)pyrimidin-2-yl]-1-(5-ethylthiophen-2-yl)-3,9-dihydro-1H-pyrido[3,4-b]indol-4-one	1421860: Inhibition of full length recombinant human N-terminal GST-tagged PDE11A4 expressed in baculovirus infected sf9 cells using FAM-cyclic-3’,5-AMP as substrate after 1 hr by fluorescence polarization assay	ic50	0.1530	uM
(10S,15S)-13-ethyl-10-(3-methylthiophen-2-yl)-8,11,13-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(9),2,4,6-tetraene-12,14-dione	1421860: Inhibition of full length recombinant human N-terminal GST-tagged PDE11A4 expressed in baculovirus infected sf9 cells using FAM-cyclic-3’,5-AMP as substrate after 1 hr by fluorescence polarization assay	ic50	0.1550	uM
(10S,15R)-13-ethyl-10-(5-ethylthiophen-2-yl)-8,11,13-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(9),2,4,6-tetraene-12,14-dione	1421860: Inhibition of full length recombinant human N-terminal GST-tagged PDE11A4 expressed in baculovirus infected sf9 cells using FAM-cyclic-3’,5-AMP as substrate after 1 hr by fluorescence polarization assay	ic50	0.1690	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, decreases methylation, affects cotreatment	4
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	3
sodium arsenite	affects methylation, increases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	increases methylation	1
zaprinast	decreases reaction, increases hydrolysis	1
trichostatin A	increases expression	1
hydroxyhydroquinone	decreases expression, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	increases methylation	1
hydroquinone	decreases expression	1
1-hydroxypyrene	affects cotreatment, decreases methylation	1
4-aminobenzhydrazide	decreases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
quinocetone	increases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Fulvestrant	increases methylation	1
Panobinostat	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

142 unique, capped per target: 135 binding, 5 admet, 1 functional, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1002089	Binding	Inhibition of human recombinant PDE11 expressed in baculovirus-infected insect Sf9 cells at 10 uM by modified two-step method	Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. — Bioorg Med Chem Lett
CHEMBL4047076	ADMET	Inhibition of human PDE11A at 100 uM	Rational design of conformationally constrained oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors. — Bioorg Med Chem
CHEMBL5723194	Functional	Affinity Biochemical interaction: (enzymatic assay, inhibition of PDE activity) EUB0002512a PDE11A	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02468193	PHASE2	COMPLETED	Study of Efficacy and Safety of Osilodrostat in Cushing’s Syndrome
NCT00001452	Not specified	COMPLETED	Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and the Carney Complex