ADCY4

Summary

ADCY4 (adenylate cyclase 4, HGNC:235) is a protein-coding gene on chromosome 14q12, encoding Adenylate cyclase type 4 (Q8NFM4). Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.

This gene encodes a member of the family of adenylate cyclases, which are membrane-associated enzymes that catalyze the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). Mouse studies show that adenylate cyclase 4, along with adenylate cyclases 2 and 3, is expressed in olfactory cilia, suggesting that several different adenylate cyclases may couple to olfactory receptors and that there may be multiple receptor-mediated mechanisms for the generation of cAMP signals. Alternative splicing results in transcript variants.

Source: NCBI Gene 196883 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 177 total — 1 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001198568

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:235
Approved symbol	ADCY4
Name	adenylate cyclase 4
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	AC4
Ensembl gene	ENSG00000129467
Ensembl biotype	protein_coding
OMIM	600292
Entrez	196883

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 10 protein_coding, 9 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000310677, ENST00000418030, ENST00000545213, ENST00000554068, ENST00000554577, ENST00000554674, ENST00000554781, ENST00000554936, ENST00000554959, ENST00000555684, ENST00000556932, ENST00000557056, ENST00000557099, ENST00000558125, ENST00000558563, ENST00000559167, ENST00000560635, ENST00000561138, ENST00000561200, ENST00000884390, ENST00000884391, ENST00000884392, ENST00000884393

RefSeq mRNA: 3 — MANE Select: NM_001198568 NM_001198568, NM_001198592, NM_139247

CCDS: CCDS9627

Canonical transcript exons

ENST00000418030 — 25 exons

Exon	Start	End
ENSE00000930135	24330168	24330295
ENSE00003467824	24325377	24325474
ENSE00003469039	24332791	24332988
ENSE00003498772	24322066	24322224
ENSE00003499557	24325818	24325887
ENSE00003505122	24329860	24330018
ENSE00003505532	24331208	24331356
ENSE00003509666	24323344	24323454
ENSE00003511569	24326299	24326342
ENSE00003525710	24319329	24319436
ENSE00003536756	24322904	24323088
ENSE00003555809	24331788	24331937
ENSE00003588658	24331018	24331129
ENSE00003591206	24332522	24332683
ENSE00003592867	24324062	24324199
ENSE00003625701	24318359	24318568
ENSE00003626932	24326079	24326165
ENSE00003638960	24318654	24318778
ENSE00003651129	24319098	24319212
ENSE00003655299	24322624	24322708
ENSE00003655974	24329061	24329234
ENSE00003667278	24324307	24324391
ENSE00003683261	24329401	24329533
ENSE00003688542	24319742	24319888
ENSE00003904577	24334494	24335071

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 98.01.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3750 / max 76.6030, expressed in 533 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142595	2.1524	507
142596	0.2227	136

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.01	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.10	gold quality
adipose tissue	UBERON:0001013	96.86	gold quality
omental fat pad	UBERON:0010414	96.77	gold quality
left uterine tube	UBERON:0001303	96.47	gold quality
right lung	UBERON:0002167	96.34	gold quality
body of uterus	UBERON:0009853	95.87	gold quality
heart left ventricle	UBERON:0002084	95.67	gold quality
thoracic mammary gland	UBERON:0005200	95.67	gold quality
mammary gland	UBERON:0001911	95.66	gold quality
myometrium	UBERON:0001296	95.57	gold quality
right lobe of thyroid gland	UBERON:0001119	95.42	gold quality
endocervix	UBERON:0000458	95.22	gold quality
upper lobe of left lung	UBERON:0008952	94.80	gold quality
spleen	UBERON:0002106	94.78	gold quality
mucosa of stomach	UBERON:0001199	94.63	gold quality
metanephros cortex	UBERON:0010533	94.60	gold quality
left lobe of thyroid gland	UBERON:0001120	94.46	gold quality
ectocervix	UBERON:0012249	94.30	gold quality
thyroid gland	UBERON:0002046	94.13	gold quality
sural nerve	UBERON:0015488	93.83	gold quality
right atrium auricular region	UBERON:0006631	93.75	gold quality
nerve	UBERON:0001021	93.52	gold quality
tibial nerve	UBERON:0001323	93.52	gold quality
heart	UBERON:0000948	93.51	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.38	gold quality
lower esophagus	UBERON:0013473	93.34	gold quality
vagina	UBERON:0000996	93.32	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.06	gold quality
uterine cervix	UBERON:0000002	92.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.11
E-MTAB-6678	yes	12.49

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR5A1, SP1, SP3

Literature-anchored findings (GeneRIF, showing 4)

• This paper reports the presence of adenylyl cyclases 2, 3, and 4 in mouse olfactory cilia. (PMID:11055432)
• The HIV-1 regulatory protein Tat was shown to inhibit the activity of adenylyl cyclase in rat microglial cells. (PMID:11299302)
• AC4 and AC2, both isoforms stimulated by Gbetagamma, are expressed in bronchial nonlipid raft membrane fractions where they colocalize with and couple to prostanoid EP2 receptors. (PMID:21228062)
• ADCY4 may be used as an epigenetic biomarker for breast cancer, as well as a possible target for therapy. (PMID:31584294)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Adcy4	ENSMUSG00000022220
rattus_norvegicus	Adcy4	ENSRNOG00000020401

Paralogs (17): GUCY1B1 (ENSG00000061918), GUCY2C (ENSG00000070019), ADCY2 (ENSG00000078295), GUCY2F (ENSG00000101890), NPR3 (ENSG00000113389), ADCY7 (ENSG00000121281), GUCY2D (ENSG00000132518), ADCY3 (ENSG00000138031), GUCY1A2 (ENSG00000152402), ADCY8 (ENSG00000155897), NPR2 (ENSG00000159899), ADCY9 (ENSG00000162104), GUCY1A1 (ENSG00000164116), ADCY1 (ENSG00000164742), NPR1 (ENSG00000169418), ADCY5 (ENSG00000173175), ADCY6 (ENSG00000174233)

Protein

Protein identifiers

Adenylate cyclase type 4 — Q8NFM4 (reviewed: Q8NFM4)

Alternative names: ATP pyrophosphate-lyase 4, Adenylate cyclase type IV, Adenylyl cyclase 4

All UniProt accessions (6): Q8NFM4, G3V258, G3V262, H0YJ57, H0YLM0, H0YN72

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.

Subcellular location. Cell membrane. Cytoplasm.

Tissue specificity. Detected in the zona glomerulosa and the zona fasciculata in the adrenal gland (at protein level).

Activity regulation. Activated by forskolin. Insensitive to calcium/calmodulin. Stimulated by GNAS and by the G-protein beta and gamma subunit complex.

Cofactor. Binds 2 magnesium ions per subunit. Is also active with manganese (in vitro).

Domain organisation. The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal modules have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two modules.

Similarity. Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NFM4-1	1	yes
Q8NFM4-2	2

RefSeq proteins (3): NP_001185497, NP_001185521, NP_640340 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001054	A/G_cyclase	Domain
IPR009398	Adcy_conserved_dom	Domain
IPR018297	A/G_cyclase_CS	Conserved_site
IPR029787	Nucleotide_cyclase	Homologous_superfamily
IPR030672	Adcy	Family
IPR032628	AC_N	Domain

Pfam: PF00211, PF06327, PF16214

Catalyzed reactions (Rhea), 1 shown:

• ATP = 3’,5’-cyclic AMP + diphosphate (RHEA:15389)

UniProt features (38 total): transmembrane region 12, binding site 12, topological domain 4, splice variant 4, modified residue 2, glycosylation site 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFM4-F1	79.03	0.36

Functional residue map

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

Ligand- & substrate-binding residues (12): 278–283; 278; 278; 279; 320–322; 322; 322; 366; 925; 1005–1007; 1012–1016; 1052

Post-translational modifications (2): 520, 536

Glycosylation sites (2): 697, 704

Function

Pathways and Gene Ontology

Reactome pathways

46 pathways

ID	Pathway
R-HSA-163359	Glucagon signaling in metabolic regulation
R-HSA-163615	PKA activation
R-HSA-164378	PKA activation in glucagon signalling
R-HSA-170660	Adenylate cyclase activating pathway
R-HSA-170670	Adenylate cyclase inhibitory pathway
R-HSA-418555	G alpha (s) signalling events
R-HSA-418594	G alpha (i) signalling events
R-HSA-418597	G alpha (z) signalling events
R-HSA-432040	Vasopressin regulates renal water homeostasis via Aquaporins
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-9634597	GPER1 signaling
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
R-HSA-111885	Opioid Signalling
R-HSA-111931	PKA-mediated phosphorylation of CREB
R-HSA-111933	Calmodulin induced events
R-HSA-111996	Ca-dependent events
R-HSA-111997	CaM pathway
R-HSA-112040	G-protein mediated events
R-HSA-112043	PLC beta mediated events
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1430728	Metabolism
R-HSA-1489509	DAG and IP3 signaling
R-HSA-162582	Signal Transduction
R-HSA-163685	Integration of energy metabolism
R-HSA-1643685	Disease
R-HSA-372790	Signaling by GPCR

MSigDB gene sets: 215 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, REACTOME_G_ALPHA_Z_SIGNALLING_EVENTS, GOBP_CELLULAR_RESPONSE_TO_FLUID_SHEAR_STRESS, GOBP_CAMP_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, REACTOME_GLUCAGON_SIGNALING_IN_METABOLIC_REGULATION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, CAGCTG_AP4_Q5, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, chr14q12

GO Biological Process (8): renal water homeostasis (GO:0003091), cAMP biosynthetic process (GO:0006171), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), intracellular signal transduction (GO:0035556), cellular response to glucagon stimulus (GO:0071377), vascular endothelial cell response to laminar fluid shear stress (GO:0097700), cyclic nucleotide biosynthetic process (GO:0009190)

GO Molecular Function (8): adenylate cyclase activity (GO:0004016), protein kinase C binding (GO:0005080), ATP binding (GO:0005524), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849)

GO Cellular Component (4): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), dendrite (GO:0030425)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
GPCR downstream signalling	3
G-protein mediated events	2
Anti-inflammatory response favouring Leishmania parasite infection	2
Integration of energy metabolism	1
PKA-mediated phosphorylation of CREB	1
Glucagon signaling in metabolic regulation	1
Activation of GABAB receptors	1
Aquaporin-mediated transport	1
Signaling by Hedgehog	1
G alpha (s) signalling events	1
Response of endothelial cells to shear stress	1
G alpha (i) signalling events	1
Calmodulin induced events	1
CaM pathway	1
PLC beta mediated events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
renal system process	1
multicellular organismal-level water homeostasis	1
purine ribonucleotide biosynthetic process	1
cyclic nucleotide biosynthetic process	1
cAMP metabolic process	1
adenylate cyclase activity	1
G protein-coupled receptor signaling pathway	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
signal transduction	1
response to glucagon	1
cellular response to peptide hormone stimulus	1
cellular response to laminar fluid shear stress	1
vascular endothelial cell response to fluid shear stress	1
nucleotide biosynthetic process	1
cyclic nucleotide metabolic process	1
cyclase activity	1
phosphorus-oxygen lyase activity	1
protein kinase binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
lyase activity	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1

Protein interactions and networks

STRING

1400 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADCY4	RAPGEF4	Q8WZA2	555
ADCY4	POLR1D	P0DPB6	541
ADCY4	GNAQ	P50148	458
ADCY4	ADCY5	O95622	457
ADCY4	ADCY8	P40145	451
ADCY4	ADCY7	P51828	427
ADCY4	NMU	P48645	425
ADCY4	OLFML1	Q6UWY5	418
ADCY4	S1PR1	P21453	412
ADCY4	PRKACA	P17612	409
ADCY4	PRKACB	P22694	402
ADCY4	IGFBP7	Q16270	400
ADCY4	PRKACG	P22612	398
ADCY4	ADCY10	Q96PN6	393
ADCY4	CCN1	O00622	392
ADCY4	CALML4	Q96GE6	392

IntAct

23 interactions, top by confidence:

A	B	Type	Score
TRIM54	ADCY4	psi-mi:“MI:0915”(physical association)	0.560
ADCY4	TTC23	psi-mi:“MI:0915”(physical association)	0.560
ADCY4	C1orf50	psi-mi:“MI:0915”(physical association)	0.560
ESRRG	ADCY4	psi-mi:“MI:0915”(physical association)	0.560
PPARG	ADCY4	psi-mi:“MI:0915”(physical association)	0.560
TTC23	ADCY4	psi-mi:“MI:0915”(physical association)	0.560
ADCY4	C1orf50	psi-mi:“MI:0915”(physical association)	0.000
ESRRG	ADCY4	psi-mi:“MI:0915”(physical association)	0.000
ADCY4	ESRRG	psi-mi:“MI:0915”(physical association)	0.000
ADCY4	PPARG	psi-mi:“MI:0915”(physical association)	0.000
	ADCY4	psi-mi:“MI:0915”(physical association)	0.000
ADCY4	brnQ3	psi-mi:“MI:0915”(physical association)	0.000
ADCY4	arsB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (7): ADCY4 (Two-hybrid), ADCY4 (Affinity Capture-MS), ADCY4 (Two-hybrid), PPARG (Two-hybrid), C1orf50 (Two-hybrid), ESRRG (Two-hybrid), ADCY4 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0U1RPR8, O02740, O08644, O09127, O15197, O19179, O73875, O73878, P0C0K6, P0C0K7, P14616, P16067, P20594, P21709, P26770, P29317, P29322, P35590, P46197, P51839, P51840, P51841, P51842, P52333, P52785, P54753, P54754, P54760, P54761, P55203, P55205, Q02846, Q03146, Q06805, Q06806, Q08345, Q1KL86, Q5JZY3, Q5SDA5, Q60750

Diamond homologs: A0A078BQP2, A0A0U1RPR8, E7EAU8, H2L002, O02298, O02740, O16715, O19179, O54865, O62179, O75343, P0A4Y1, P16065, P16066, P16068, P18293, P18910, P19686, P19687, P20594, P20595, P22717, P23897, P25092, P26770, P33402, P51840, P51841, P51842, P52785, P55202, P55203, P55204, P70106, P90895, P91550, P92006, P9WQ34, P9WQ35, Q02108

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NF1	up-regulates	ADCY4
ADCY4	“up-regulates quantity”	“3’,5’-cyclic AMP”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	141
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
442398	GRCh37/hg19 14q11.2-12(chr14:24233721-31377083)x1	Pathogenic
2685479	GRCh37/hg19 14q11.2-12(chr14:24445622-28262222)x1	Likely pathogenic

SpliceAI

5167 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24318652:A:AC	donor_gain	1.0000
14:24318653:C:CC	donor_gain	1.0000
14:24319244:A:T	acceptor_gain	1.0000
14:24319323:CCGTA:C	donor_loss	1.0000
14:24319324:CGTA:C	donor_loss	1.0000
14:24319325:GTA:G	donor_loss	1.0000
14:24319326:TACC:T	donor_loss	1.0000
14:24319327:A:C	donor_loss	1.0000
14:24319328:C:A	donor_loss	1.0000
14:24319432:AGCAG:A	acceptor_gain	1.0000
14:24319433:GCAG:G	acceptor_gain	1.0000
14:24319434:CAG:C	acceptor_gain	1.0000
14:24319434:CAGC:C	acceptor_gain	1.0000
14:24319435:AG:A	acceptor_gain	1.0000
14:24319436:GC:G	acceptor_loss	1.0000
14:24319437:C:CC	acceptor_gain	1.0000
14:24319437:CT:C	acceptor_loss	1.0000
14:24319438:T:A	acceptor_loss	1.0000
14:24319762:T:C	donor_gain	1.0000
14:24322019:AGGC:A	donor_gain	1.0000
14:24322246:C:CT	acceptor_gain	1.0000
14:24324061:CCAGG:C	donor_gain	1.0000
14:24325475:C:CC	acceptor_gain	1.0000
14:24326077:A:AC	donor_gain	1.0000
14:24326078:C:CC	donor_gain	1.0000
14:24326078:CTT:C	donor_gain	1.0000
14:24326080:T:TA	donor_gain	1.0000
14:24329399:AC:A	donor_gain	1.0000
14:24329400:CC:C	donor_gain	1.0000
14:24329431:C:A	donor_gain	1.0000

AlphaMissense

6931 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24318688:C:G	R1016P	1.000
14:24318694:G:T	A1014D	1.000
14:24318699:G:C	N1012K	1.000
14:24318699:G:T	N1012K	1.000
14:24318714:C:A	W1007C	1.000
14:24318714:C:G	W1007C	1.000
14:24318716:A:G	W1007R	1.000
14:24318716:A:T	W1007R	1.000
14:24318721:T:A	D1005V	1.000
14:24318725:A:C	Y1004D	1.000
14:24318742:C:T	G998E	1.000
14:24318743:C:A	G998W	1.000
14:24318743:C:G	G998R	1.000
14:24318743:C:T	G998R	1.000
14:24319098:C:A	G986W	1.000
14:24319379:A:C	Y931D	1.000
14:24319395:C:A	K925N	1.000
14:24319395:C:G	K925N	1.000
14:24319746:T:A	D910V	1.000
14:24319747:C:G	D910H	1.000
14:24319770:A:G	L902P	1.000
14:24319847:G:C	F876L	1.000
14:24319847:G:T	F876L	1.000
14:24319849:A:G	F876L	1.000
14:24319854:A:T	V874D	1.000
14:24322115:A:G	L846P	1.000
14:24329522:A:T	I410N	1.000
14:24329909:A:G	S390P	1.000
14:24329910:C:A	W389C	1.000
14:24329910:C:G	W389C	1.000

dbSNP variants (sampled 300 via entrez): RS1000125361 (14:24321788 C>T), RS1000305647 (14:24336474 G>A), RS1000433857 (14:24321060 G>A), RS1000675087 (14:24319871 G>A), RS1001129793 (14:24336745 C>T), RS1001178411 (14:24331051 A>T), RS1001194282 (14:24331594 A>C,G), RS1001457310 (14:24334378 G>A,C), RS1001629291 (14:24318584 G>A,C), RS1002176704 (14:24319953 G>A,C,T), RS1002191902 (14:24328598 G>A,T), RS1002244467 (14:24334678 G>A,C,T), RS1002318248 (14:24323073 A>G), RS1002385213 (14:24325683 A>G), RS1002400325 (14:24331305 C>A,T)

Disease associations

OMIM: gene MIM:600292 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002371_1	Parent of origin effect on language impairment (paternal)	4.000000e-08
GCST012227_602	Hip circumference adjusted for BMI	4.000000e-08
GCST90000025_529	Appendicular lean mass	8.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2097167 (PROTEIN FAMILY)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Adenylyl cyclases (ACs)

ChEMBL bioactivities

24 potent at pChembl≥5 of 24 total, top 24 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.06	Ki	0.88	nM	CHEMBL3142312
8.77	Ki	1.7	nM	CHEMBL3142318
8.77	Ki	1.7	nM	CHEMBL3142332
8.72	Ki	1.9	nM	CHEMBL3142329
8.60	Ki	2.5	nM	CHEMBL3142331
8.59	Ki	2.6	nM	CHEMBL2369777
8.41	Ki	3.9	nM	CHEMBL2369525
8.38	Ki	4.2	nM	CHEMBL2369778
8.11	Ki	7.8	nM	CHEMBL3142313
7.85	Ki	14	nM	CHEMBL66087
7.77	Ki	17	nM	CHEMBL418135
7.70	Ki	20	nM	CHEMBL293907
7.54	Ki	29	nM	CHEMBL305151
7.48	Ki	33	nM	CHEMBL62123
7.16	Ki	69	nM	CHEMBL305151
7.15	EC50	71	nM	(R)-SKF-38393
6.96	Ki	110	nM	CHEMBL62412
6.84	Ki	144	nM	CHEMBL64475
6.59	Ki	254	nM	CHEMBL62444
6.52	Ki	300	nM	CHEMBL62892
6.50	Ki	317	nM	CHEMBL64646
6.21	Ki	610	nM	CHEMBL418468
6.00	Ki	1000	nM	CHEMBL64955
5.28	EC50	5200	nM	CHEMBL57873

PubChem BioAssay actives

24 with measured affinity, of 52 total; 23 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
(4R,7S,10S,13S,16S)-N-[(2R)-1-[[(2R)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0009	uM
(4R,7S,10S,13S,16S)-N-[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0017	uM
(4R,7S,10S,13S,16S)-N-[(2S)-1-[[(2R)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0017	uM
(4R,7S,10S,13S,16S)-N-[(2R)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0019	uM
(4R,7S,10S,13S,16S)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34312: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0025	uM
(4R,7S,10S,13S,16R)-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-N-[(2S)-5-(diaminomethylideneamino)-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-1-oxopentan-2-yl]-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0026	uM
(2S)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-1-[(4R,7S,10S,13S,16R)-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]pyrrolidine-2-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0039	uM
(4R,7S,10S,13S,16R)-N-[(2S)-6-amino-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0042	uM
(2S)-2-[[(2S)-2-[[(4R,7S,10S,13S,16S)-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0078	uM
3-[[4-[1-[4-(2,4-dichlorophenyl)anilino]-1-oxooctan-2-yl]oxybenzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0140	uM
3-[[4-[1-[4-(1-benzofuran-2-yl)anilino]-1-oxooctan-2-yl]oxybenzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0170	uM
3-[[4-[2-[[4-(1-benzofuran-2-yl)phenyl]carbamoyl]octyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0200	uM
3-[[4-[3-[4-(1-benzofuran-2-yl)anilino]-2-(4-tert-butylphenyl)-3-oxopropyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0290	uM
3-[[4-[2-(4-tert-butylphenyl)-3-[4-(2,4-dichlorophenyl)anilino]-3-oxopropyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0330	uM
(5R)-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol	34592: Compound was tested for the adenylate cyclase stimulation	ec50	0.0710	uM
3-[[4-[2-(4-tert-butylphenyl)-3-oxo-3-[4-(trifluoromethoxy)anilino]propyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.1100	uM
3-[[4-[1-(4-tert-butylphenyl)-2-oxo-2-(4-phenylanilino)ethoxy]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.1440	uM
3-[[4-[[(4-tert-butylcyclohexyl)-[[4-(trifluoromethoxy)phenyl]carbamoyl]amino]methyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.2540	uM
3-[[4-[2-(4-tert-butylphenyl)-3-oxo-3-(4-phenylanilino)propyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.3000	uM
4-[1-(4-tert-butylphenyl)-2-oxo-2-(4-phenylanilino)ethoxy]-N-(2H-tetrazol-5-yl)benzamide	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.3170	uM
3-[[4-[2-(4-tert-butylphenyl)-3-oxo-3-(quinolin-3-ylamino)propyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.6100	uM
3-[[4-[2-(4-tert-butylphenyl)-3-[4-(hydroxymethyl)anilino]-3-oxopropyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	1.0000	uM
2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol	34592: Compound was tested for the adenylate cyclase stimulation	ec50	5.2000	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, affects cotreatment, decreases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
arsenite	increases methylation	1
perfluorooctanoic acid	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
clothianidin	decreases expression	1
abrine	increases expression	1
perfluorobutanesulfonic acid	affects expression	1
bisphenol S	decreases expression, affects cotreatment	1
Benzo(a)pyrene	increases methylation	1
Dexamethasone	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ozone	affects expression, increases abundance	1
Silicon Dioxide	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Dronabinol	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

16 unique, capped per target: 14 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3284336	Binding	Agonist activity at adenylyl cyclase (unknown origin) at 1.35 x 10’-4 M	Synthesis of a fragment of human parathyroid hormore, hPTH-(44-68). — J Med Chem
CHEMBL645298	Functional	In vitro antagonist activity was measured by inhibition of vasopressin-stimulated adenylate cyclase in renal medullary preparation in pig	Dicarbavasopressin antagonist analogues exhibit reduced in vivo agonist activity. — J Med Chem

Clinical trials (associated diseases)

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