RAPGEF4

Summary

RAPGEF4 (Rap guanine nucleotide exchange factor 4, HGNC:16626) is a protein-coding gene on chromosome 2q31.1, encoding Rap guanine nucleotide exchange factor 4 (Q8WZA2). Guanine nucleotide exchange factor (GEF) for RAP1A, RAP1B and RAP2A small GTPases that is activated by binding cAMP.

Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in Ras protein signal transduction; regulation of neurotransmitter receptor localization to postsynaptic specialization membrane; and regulation of postsynapse organization. Predicted to act upstream of or within with a positive effect on hormone secretion. Predicted to act upstream of or within adenylate cyclase-activating G protein-coupled receptor signaling pathway; regulation of exocytosis; and secretion by cell. Predicted to be located in membrane. Predicted to be active in several cellular components, including glutamatergic synapse; hippocampal mossy fiber to CA3 synapse; and postsynaptic density. Implicated in autistic disorder.

Source: NCBI Gene 11069 — RefSeq curated summary.

At a glance

• Gene–disease (curated): prostate cancer (Limited, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 150 total
• Druggable target: yes
• MANE Select transcript: NM_007023

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16626
Approved symbol	RAPGEF4
Name	Rap guanine nucleotide exchange factor 4
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Aliases	cAMP-GEFII, CGEF2
Ensembl gene	ENSG00000091428
Ensembl biotype	protein_coding
OMIM	606058
Entrez	11069

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 14 protein_coding, 6 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000397081, ENST00000397085, ENST00000397087, ENST00000409036, ENST00000459852, ENST00000464976, ENST00000466030, ENST00000473003, ENST00000473043, ENST00000473182, ENST00000484331, ENST00000484645, ENST00000535187, ENST00000538974, ENST00000540783, ENST00000907812, ENST00000907813, ENST00000907814, ENST00000907815, ENST00000931068, ENST00000970620, ENST00000970621

RefSeq mRNA: 16 — MANE Select: NM_007023 NM_001100397, NM_001282899, NM_001282900, NM_001282901, NM_001375864, NM_001375865, NM_001375866, NM_001375867, NM_001375868, NM_001375869, NM_001375870, NM_001375871, NM_001375872, NM_001375873, NM_001375874, NM_007023

CCDS: CCDS42775, CCDS42776, CCDS63060, CCDS63061, CCDS74604, CCDS92899

Canonical transcript exons

ENST00000397081 — 31 exons

Exon	Start	End
ENSE00001527250	173051640	173052893
ENSE00001857901	172735845	172736048
ENSE00003271466	173033914	173033964
ENSE00003291569	173030164	173030254
ENSE00003337028	173017426	173017504
ENSE00003362632	172996466	172996554
ENSE00003366543	173001266	173001344
ENSE00003368337	173017174	173017204
ENSE00003372603	173016349	173016437
ENSE00003377988	173027081	173027259
ENSE00003378215	173018656	173018802
ENSE00003379029	173020618	173020715
ENSE00003382320	173014464	173014614
ENSE00003403603	173036125	173036212
ENSE00003416842	173026572	173026697
ENSE00003419420	173036628	173036692
ENSE00003437050	173048600	173048654
ENSE00003459743	172922281	172922300
ENSE00003482359	172983496	172983580
ENSE00003494562	172985433	172985493
ENSE00003511871	172988693	172988839
ENSE00003514600	172961122	172961228
ENSE00003548392	172967261	172967444
ENSE00003580212	172965562	172965683
ENSE00003635503	172917802	172917874
ENSE00003644207	172988196	172988272
ENSE00003645888	172960760	172960813
ENSE00003667134	172814279	172814425
ENSE00003671299	172797525	172797613
ENSE00003677307	172795025	172795167
ENSE00003679481	172990810	172990925

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 98.68.

FANTOM5 (CAGE): breadth broad, TPM avg 6.2853 / max 502.3765, expressed in 452 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23726	1.9480	136
23722	1.0609	170
23721	0.6971	124
23725	0.5073	97
23729	0.3752	156
23737	0.3691	95
23717	0.2004	69
23728	0.1817	82
23736	0.1341	38
23719	0.1190	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	98.68	gold quality
amygdala	UBERON:0001876	98.51	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.73	gold quality
prefrontal cortex	UBERON:0000451	97.64	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.46	gold quality
cingulate cortex	UBERON:0003027	97.35	gold quality
Ammon’s horn	UBERON:0001954	97.30	gold quality
anterior cingulate cortex	UBERON:0009835	97.29	gold quality
temporal lobe	UBERON:0001871	96.73	gold quality
nucleus accumbens	UBERON:0001882	96.59	gold quality
right adrenal gland	UBERON:0001233	96.44	gold quality
frontal cortex	UBERON:0001870	96.41	gold quality
left adrenal gland	UBERON:0001234	96.40	gold quality
right adrenal gland cortex	UBERON:0035827	96.33	gold quality
left adrenal gland cortex	UBERON:0035825	96.20	gold quality
CA1 field of hippocampus	UBERON:0003881	96.19	gold quality
cerebral cortex	UBERON:0000956	95.82	gold quality
adrenal cortex	UBERON:0001235	95.78	gold quality
neocortex	UBERON:0001950	95.78	gold quality
telencephalon	UBERON:0001893	95.40	gold quality
entorhinal cortex	UBERON:0002728	95.37	gold quality
orbitofrontal cortex	UBERON:0004167	95.34	gold quality
adrenal gland	UBERON:0002369	95.24	gold quality
endothelial cell	CL:0000115	95.00	gold quality
superior frontal gyrus	UBERON:0002661	94.87	gold quality
postcentral gyrus	UBERON:0002581	94.47	gold quality
putamen	UBERON:0001874	94.13	gold quality
parietal lobe	UBERON:0001872	94.03	gold quality
caudate nucleus	UBERON:0001873	93.68	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.65	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	57.14
E-CURD-119	yes	33.59
E-ANND-3	yes	14.91
E-MTAB-5061	no	3.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

87 targeting RAPGEF4, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4789-3P	99.99	70.75	2484
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-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-130A-3P	99.90	73.31	1861

Literature-anchored findings (GeneRIF, showing 31)

• Mutations in the hinge of Epac can uncouple cAMP binding from its exchange activity. (PMID:12469113)
• variants were present in five families, where they segregate with the autistic phenotype. (PMID:14593429)
• a novel protein-binding partner for EPAC1 and EPAC2, light chain 2 of MAP1A (microtubule-associated protein 1A) (PMID:15202935)
• Epac1 and Epac2 induce a potent activation of the Ca2+-sensitive big K+ channel, slight membrane hyperpolarization, and increased after-hyperpolarization in cultured cerebellar granule cells. These effects involve activation of Rap and p38 MAPK. (PMID:17284589)
• Epac1 and Epac2 were expressed at the brush border of proximal tubules cells and in the thick ascending limbs of Henle’s loop. (PMID:18495799)
• Epac2 signaling plays a stimulatory role in pancreatic and intestinal endocrine cells, including proglucagon transcription and glucagon and GLP-1 production. (PMID:18854429)
• Substitution of the conserved phenylalanine 435 with glycine facilitates the hinge bending and leads to a constitutively active Epac2 capable of stimulating nucleotide exchange in the absence of cAMP. (PMID:19553663)
• An important time-limited role is identified for hippocampal Epac2 signaling in cognition, opening new avenues to investigate the molecular mechanisms underlying memory retrieval. (PMID:19739231)
• Studies demonstrate the occurrence of the EPAC2 splicing variant EPAC2B in adrenocortical cancer cells and reveal the involvement of EPAC2B in cAMP-induced effects on cytoskeleton integrity and cell migration. (PMID:20233795)
• Epac2 & Epac1 signaling pathways may be associated with cAMP-mediated functional differentiation and syncytialization of trophoblasts. Expression of Epac2 & Epac 1 in placenta at different stages was investigated. (PMID:20663796)
• Mechanism of intracellular cAMP sensor Epac2 activation: cAMP-induced conformational changes identified by amide hydrogen/deuterium exchange mass spectrometry (PMID:21454623)
• Cigarette smoke extract decreased Epac1 expression, but did not affect Epac2 and PKA expression. (PMID:22363678)
• data show the expression of EPAC is blunted in HPRT-deficient neuron-like cell lines and fibroblast cells from Lesch-Nyhan syndrome (LNS) patients; propose that the alterations in EPAC/RAP1 signaling and cell migration in HPRT deficiency are crucial for neuro-developmental events that may contribute to neurological dysfunctions in LNS (PMID:23804752)
• EPAC2-mediated CRT expression is essential for the functional and morphological differentiation of endometrial stromal cells into decidual cells (PMID:24169561)
• EPAC1 and EPAC2 are critical signaling intermediates in osteoclast differentiation that permit RANKL-stimulated NFkB nuclear translocation and actin rearrangements (PMID:25122553)
• Follow-up replication analyses in up to an additional 21,345 participants identified three new fasting plasma glucose loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. (PMID:25187374)
• CALR regulated by EPAC2 in endometrial glandular epithelial cells is critical for the expression of LIF and PTGS2-mediated production of PGE2 through cAMP signaling. (PMID:25378661)
• Identified a conserved nuclear pore localisation signal (NPLS; amino acids 764-838 of EPAC1) in the catalytic domains of the cAMP-sensors, EPAC1 and EPAC2A. EPAC1 and EPAC2, display distinct subcellular distributions. (PMID:25683912)
• Data show that Epac2 is activated by cAMP and changes its structure. It is involved in cAMP-mediated signal transduction through activation of the Ras-like small GTPase and is expressed mainly in brain, neuroendocrine and endocrine tissues. [review] (PMID:26390815)
• This review focus is on the function of Epac in the heart. Accumulating evidence has revealed that both Epac1 and Epac2 play important roles in the structure and function of the heart under physiological and pathological conditions. [review] (PMID:27549789)
• rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer’s disease (AD) patients, was significantly correlated with apathy and mood disturbance (PMID:27598965)
• Study identifies Epac2-Rap1 signaling as a novel feedback mechanism in the heart, which controls mitochondrial reactive oxygen species production. (PMID:27649969)
• Cyclic AMP (cAMP), a secondary messenger responsible for various physiological processes regulates cell metabolism by activating Protein kinase A (PKA) and by targeting exchange protein directly activated by cAMP (EPAC). EPAC is present in two isoforms EPAC1 and EPAC2, which exhibit different tissue distribution and is involved in GDP/GTP exchange along with activating Rap1- and Rap2-mediated signaling pathways. (PMID:29417338)
• Through isoform-specific gene knockdown, the authors found that EPAC2, but not EPAC1, plays a dominant role in controlling RSV replication and virus-induced host responses. (PMID:30185593)
• The authors conclude that Epac2/cAMP controls fusion pore expansion and thus the balance of hormone and transmitter release during insulin granule exocytosis. (PMID:31099751)
• The Epac2 coding gene (RAPGEF4) rs3769219 polymorphism is associated with protection against major depressive disorder in the Chinese Han population. (PMID:32905835)
• Epac: new emerging cAMP-binding protein. (PMID:33298248)
• Broad Impact of Exchange Protein Directly Activated by cAMP 2 (EPAC2) on Respiratory Viral Infections. (PMID:34205489)
• Pancreatic cancer-derived exosomal microRNA-19a induces beta-cell dysfunction by targeting ADCY1 and EPAC2. (PMID:34512170)
• Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis. (PMID:34685730)
• EPAC Regulates Melanoma Growth by Stimulating mTORC1 Signaling and Loss of EPAC Signaling Dependence Correlates with Melanoma Progression. (PMID:35834616)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rapgef4b	ENSDARG00000075924
danio_rerio	rapgef4a	ENSDARG00000079872
mus_musculus	Rapgef4	ENSMUSG00000049044
rattus_norvegicus	Rapgef4	ENSRNOG00000001516

Paralogs (24): RASGRF1 (ENSG00000058335), RASGRP2 (ENSG00000068831), RAPGEF3 (ENSG00000079337), SOS2 (ENSG00000100485), RAPGEF1 (ENSG00000107263), RAPGEFL1 (ENSG00000108352), RAPGEF2 (ENSG00000109756), RASGRF2 (ENSG00000113319), SOS1 (ENSG00000115904), RALGPS2 (ENSG00000116191), RAPGEF5 (ENSG00000136237), RALGPS1 (ENSG00000136828), RASGEF1B (ENSG00000138670), RGL1 (ENSG00000143344), RASGEF1C (ENSG00000146090), RASGRP3 (ENSG00000152689), RAPGEF6 (ENSG00000158987), RGL4 (ENSG00000159496), RALGDS (ENSG00000160271), RASGRP4 (ENSG00000171777), RASGRP1 (ENSG00000172575), RASGEF1A (ENSG00000198915), RGL3 (ENSG00000205517), RGL2 (ENSG00000237441)

Protein

Protein identifiers

Rap guanine nucleotide exchange factor 4 — Q8WZA2 (reviewed: Q8WZA2)

Alternative names: Exchange factor directly activated by cAMP 2, Exchange protein directly activated by cAMP 2, cAMP-regulated guanine nucleotide exchange factor II

All UniProt accessions (4): Q8WZA2, B7Z278, E9PB94, H7BYQ0

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) for RAP1A, RAP1B and RAP2A small GTPases that is activated by binding cAMP. Does not seem to activate RAB3A. Involved in cAMP-dependent, PKA-independent exocytosis through interaction with RIMS2.

Subunit / interactions. Interacts with RIMS1 and RIMS2. Probably part of a complex with RIMS2 and GTP-activated RAB3A.

Subcellular location. Cytoplasm. Membrane.

Tissue specificity. Predominantly expressed in brain and adrenal gland. Isoform 2 is expressed in liver. Isoform 1 is expressed in liver at very low levels.

Domain organisation. The N-terminal nucleotide phosphate binding region cAMP 1 has a much lower affinity for cAMP as compared to cAMP 2. The DEP domain is involved in membrane localization independent from regulation by cAMP.

Miscellaneous. Produced by alternative promoter usage. Promoter analysis was carried out in mouse. Produced by alternative promoter usage. Promoter analysis was carried out in mouse. Produced by alternative splicing of isoform 1.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8WZA2-1	1	yes
Q8WZA2-2	2
Q8WZA2-3	3
Q8WZA2-4	4
Q8WZA2-5	5

RefSeq proteins (16): NP_001093867, NP_001269828, NP_001269829, NP_001269830, NP_001362793, NP_001362794, NP_001362795, NP_001362796, NP_001362797, NP_001362798, NP_001362799, NP_001362800, NP_001362801, NP_001362802, NP_001362803, NP_008954* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000591	DEP_dom	Domain
IPR000595	cNMP-bd_dom	Domain
IPR000651	Ras-like_Gua-exchang_fac_N	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR008937	Ras-like_GEF	Family
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR019804	Ras_G-nucl-exch_fac_CS	Conserved_site
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily

Pfam: PF00027, PF00610, PF00617, PF00618

UniProt features (18 total): sequence conflict 7, splice variant 5, domain 3, binding site 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WZA2-F1	87.41	0.63

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 (2): 422–425; 432–433

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-354192	Integrin signaling
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-392517	Rap1 signalling
R-HSA-422356	Regulation of insulin secretion
R-HSA-109582	Hemostasis
R-HSA-1280218	Adaptive Immune System
R-HSA-1430728	Metabolism
R-HSA-162582	Signal Transduction
R-HSA-163685	Integration of energy metabolism
R-HSA-168256	Immune System
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76009	Platelet Aggregation (Plug Formation)

MSigDB gene sets: 285 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, BENPORATH_ES_WITH_H3K27ME3, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, TGCACTT_MIR519C_MIR519B_MIR519A, REACTOME_PLATELET_AGGREGATION_PLUG_FORMATION, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_INSULIN_SECRETION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOMF_GTPASE_BINDING, AAAYRNCTG_UNKNOWN, TANG_SENESCENCE_TP53_TARGETS_UP

GO Biological Process (15): adaptive immune response (GO:0002250), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), Ras protein signal transduction (GO:0007265), calcium-ion regulated exocytosis (GO:0017156), regulation of exocytosis (GO:0017157), insulin secretion (GO:0030073), positive regulation of insulin secretion (GO:0032024), regulation of synaptic vesicle cycle (GO:0098693), exocytosis (GO:0006887), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), small GTPase-mediated signal transduction (GO:0007264), intracellular signal transduction (GO:0035556), hormone secretion (GO:0046879), regulation of insulin secretion (GO:0050796)

GO Molecular Function (6): guanyl-nucleotide exchange factor activity (GO:0005085), cAMP binding (GO:0030552), protein-macromolecule adaptor activity (GO:0030674), small GTPase binding (GO:0031267), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (5): cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), hippocampal mossy fiber to CA3 synapse (GO:0098686), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signal Transduction	1
Platelet Aggregation (Plug Formation)	1
Regulation of insulin secretion	1
Adaptive Immune System	1
Integration of energy metabolism	1
Immune System	1
Metabolism	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
signal transduction	2
regulation of vesicle-mediated transport	2
insulin secretion	2
intracellular anatomical structure	2
immune response	1
G protein-coupled receptor activity	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
small GTPase-mediated signal transduction	1
regulated exocytosis	1
exocytosis	1
regulation of secretion by cell	1
protein secretion	1
peptide hormone secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
synaptic vesicle cycle	1
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
adenylate cyclase activity	1
G protein-coupled receptor signaling pathway	1
intracellular signaling cassette	1
hormone transport	1
signal release	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
cyclic nucleotide binding	1
adenyl ribonucleotide binding	1
anion binding	1
protein binding	1
molecular adaptor activity	1
GTPase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1

Protein interactions and networks

STRING

1902 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAPGEF4	PRKACA	P17612	968
RAPGEF4	PRKACB	P22694	967
RAPGEF4	PRKACG	P22612	967
RAPGEF4	LRPAP1	P30533	950
RAPGEF4	ARRB2	P32121	945
RAPGEF4	ARRB1	P49407	945
RAPGEF4	RIMS2	Q9UQ26	929
RAPGEF4	RAP1B	P09526	922
RAPGEF4	ALDH7A1	P49419	908
RAPGEF4	RABIF	P47224	884
RAPGEF4	PCLO	Q9Y6V0	880
RAPGEF4	ABCC8	Q09428	868
RAPGEF4	RAP2A	P10114	865
RAPGEF4	RAP1A	P10113	857
RAPGEF4	RIMS1	Q86UR5	835

IntAct

37 interactions, top by confidence:

A	B	Type	Score
	PRKAR1A	psi-mi:“MI:0914”(association)	0.700
RAPGEF4	BMERB1	psi-mi:“MI:0915”(physical association)	0.670
BMERB1	RAPGEF4	psi-mi:“MI:0915”(physical association)	0.670
RAPGEF4	SWAP70	psi-mi:“MI:0915”(physical association)	0.670
RAPGEF4	DEF6	psi-mi:“MI:0915”(physical association)	0.560
RAPGEF4	SSB	psi-mi:“MI:0915”(physical association)	0.560
RAPGEF4	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
HTT	RAPGEF4	psi-mi:“MI:0915”(physical association)	0.560
RAPGEF4	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF4	MAGT1	psi-mi:“MI:0915”(physical association)	0.400
SLC22A7	RAPGEF4	psi-mi:“MI:0915”(physical association)	0.370
RAPGEF4	BZRAP1	psi-mi:“MI:0915”(physical association)	0.370
RAPGEF4	TRAF2	psi-mi:“MI:0915”(physical association)	0.370
RAPGEF4	ZC3H11A	psi-mi:“MI:0915”(physical association)	0.370
METTL3	TUBAL3	psi-mi:“MI:0914”(association)	0.350
SHANK3	IGKV3D-15	psi-mi:“MI:0914”(association)	0.350

BioGRID (25): C16orf45 (Two-hybrid), RAPGEF4 (Affinity Capture-MS), RAPGEF4 (Reconstituted Complex), RAPGEF4 (Affinity Capture-Western), RAPGEF4 (Affinity Capture-Western), RAPGEF4 (Affinity Capture-MS), RAPGEF4 (Affinity Capture-MS), RAPGEF4 (Two-hybrid), MAGT1 (Proximity Label-MS), RAP2A (Biochemical Activity), RAP1A (Biochemical Activity), RIMS2 (Affinity Capture-Western), RAPGEF4 (Affinity Capture-RNA), RAPGEF4 (Affinity Capture-MS), RAPGEF4 (Affinity Capture-MS)

ESM2 similar proteins: A0JN86, A2AHJ4, A2APV2, A2AQW0, A9JRL3, B3DK16, O08874, O35099, P0CF52, P19447, P23798, P25916, P32866, P35226, P35227, P49135, Q07139, Q1JPS1, Q1RMT1, Q21029, Q28H21, Q2YDF9, Q32KX7, Q3UK78, Q4QR06, Q5R8L2, Q5RA62, Q5SDR3, Q5ZKK7, Q640D5, Q6DD21, Q6DLV9, Q6GN16, Q6RI45, Q6ZN16, Q7T3E6, Q7Z569, Q7ZYZ7, Q86SE9, Q8BPM2

Diamond homologs: A1CEE0, A1DFV9, A4R596, O75140, P61460, Q0CHV5, Q1E9Q9, Q2H0S0, Q2UMR9, Q4WHH4, Q54XA2, Q570Y9, Q5AW24, Q7S9J6, Q8TB45, Q8WZA2, Q9W0E3, A2AWR3, Q3LAC4, Q4PE51, Q5R9A7, Q69ZK0, Q6CWI2, Q70Z35, Q7Z3F1, Q8TCU6, Q9EQZ6, A3LRB2, P47170, Q05AS8, Q54M77, Q5AIA4, Q6BN00, Q6CAP3, Q6FK84, Q75DV2, A0JM95, A4IFE4, F1M386, F1MSG6

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
“3’,5’-cyclic AMP”	“up-regulates activity”	RAPGEF4	binding
RAPGEF4	“up-regulates quantity”	INS	relocalization
RAPGEF4	“up-regulates quantity”	ABCC8	binding
RAPGEF4	“up-regulates quantity”	RAP1A	binding
RAPGEF4	“up-regulates activity”	RAP1A	“guanine nucleotide exchange factor”
RAPGEF4	“up-regulates activity”	RAP1B	“guanine nucleotide exchange factor”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	119
Likely benign	5
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

6334 predictions. Top by Δscore:

Variant	Effect	Δscore
2:172795019:A:AG	acceptor_gain	1.0000
2:172795020:T:G	acceptor_gain	1.0000
2:172795021:A:AG	acceptor_gain	1.0000
2:172795021:ACAGA:A	acceptor_loss	1.0000
2:172795022:C:G	acceptor_gain	1.0000
2:172795022:CA:C	acceptor_loss	1.0000
2:172795023:A:AG	acceptor_gain	1.0000
2:172795023:AGA:A	acceptor_loss	1.0000
2:172795024:G:GT	acceptor_gain	1.0000
2:172795024:GA:G	acceptor_gain	1.0000
2:172795024:GAC:G	acceptor_gain	1.0000
2:172795024:GACC:G	acceptor_gain	1.0000
2:172795024:GACCA:G	acceptor_gain	1.0000
2:172795077:G:GT	donor_gain	1.0000
2:172795081:T:G	donor_gain	1.0000
2:172795159:G:T	donor_gain	1.0000
2:172795167:TG:T	donor_loss	1.0000
2:172795168:G:GA	donor_loss	1.0000
2:172795168:G:GG	donor_gain	1.0000
2:172795169:T:A	donor_loss	1.0000
2:172797523:A:AG	acceptor_gain	1.0000
2:172797524:G:GG	acceptor_gain	1.0000
2:172797524:GT:G	acceptor_gain	1.0000
2:172814274:CTCAG:C	acceptor_loss	1.0000
2:172814275:TCAGG:T	acceptor_loss	1.0000
2:172814276:CAGGA:C	acceptor_loss	1.0000
2:172814277:A:AG	acceptor_gain	1.0000
2:172814277:AG:A	acceptor_gain	1.0000
2:172814278:G:GG	acceptor_gain	1.0000
2:172814278:GG:G	acceptor_gain	1.0000

AlphaMissense

6667 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:172797554:T:A	W80R	1.000
2:172797554:T:C	W80R	1.000
2:172814322:G:A	G114E	1.000
2:172814385:T:C	L135P	1.000
2:172988198:T:C	F385L	1.000
2:172988199:T:C	F385S	1.000
2:172988200:T:A	F385L	1.000
2:172988200:T:G	F385L	1.000
2:172988216:G:C	G391R	1.000
2:172988225:T:A	W394R	1.000
2:172988225:T:C	W394R	1.000
2:172988227:G:C	W394C	1.000
2:172988227:G:T	W394C	1.000
2:172988243:G:A	G400R	1.000
2:172988243:G:C	G400R	1.000
2:172988256:T:A	V404E	1.000
2:172988700:T:A	V412D	1.000
2:172988709:T:C	L415P	1.000
2:172988726:T:C	F421L	1.000
2:172988727:T:C	F421S	1.000
2:172988727:T:G	F421C	1.000
2:172988728:C:A	F421L	1.000
2:172988728:C:G	F421L	1.000
2:172988729:G:C	G422R	1.000
2:172988729:G:T	G422C	1.000
2:172988730:G:A	G422D	1.000
2:172988730:G:T	G422V	1.000
2:172988736:T:C	L424S	1.000
2:172988739:C:A	A425E	1.000
2:172988742:T:A	L426Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000012561 (2:173030104 A>T), RS1000028886 (2:172852722 G>A), RS1000040026 (2:173035185 G>A), RS1000040869 (2:172759555 C>T), RS1000041917 (2:172802948 A>G), RS1000044891 (2:172893033 A>T), RS1000048674 (2:172755676 G>A,T), RS1000052952 (2:172766033 T>A), RS1000075007 (2:172977582 C>A), RS1000087643 (2:172936895 A>G), RS1000109102 (2:172809528 C>T), RS1000119908 (2:172815580 A>T), RS1000125387 (2:172900659 A>T), RS1000160387 (2:172893298 C>A,T), RS1000165378 (2:172839904 C>T)

Disease associations

OMIM: gene MIM:606058 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
prostate cancer	Limited	Autosomal dominant

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002586_1	Fasting plasma glucose	7.000000e-11
GCST002761_19	Hippocampal volume	9.000000e-06
GCST005164_1	GLP-1 levels in response to oral glucose tolerance test (fasting)	2.000000e-06
GCST008595_59	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	2.000000e-09
GCST009218_44	Lateral ventricle temporal horn volume	3.000000e-06
GCST010242_442	HDL cholesterol levels	3.000000e-11
GCST011587_6	Fasting blood glucose	8.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005035	hippocampal volume
EFO:0004307	glucose tolerance test
EFO:0008465	glucagon-like peptide-1 measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2029198 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Exchange proteins activated by cyclic AMP (EPACs)

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
HJC 0350	Inhibition	6.5	pIC50
ESI-09	Inhibition	5.15	pIC50

ChEMBL bioactivities

91 potent at pChembl≥5 of 115 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.52	IC50	300	nM	CHEMBL2313646
6.40	IC50	400	nM	CHEMBL2313637
6.40	IC50	400	nM	CHEMBL2313653
6.40	IC50	400	nM	CHEMBL3808606
6.40	IC50	400	nM	CHEMBL3809313
6.30	IC50	500	nM	CHEMBL2313639
6.30	IC50	500	nM	CHEMBL2313653
6.30	IC50	500	nM	CHEMBL3808936
6.30	IC50	500	nM	CHEMBL3808997
6.22	IC50	600	nM	CHEMBL3260989
6.22	IC50	600	nM	CHEMBL3809121
6.16	IC50	700	nM	CHEMBL2313654
6.16	IC50	700	nM	CHEMBL3808792
6.05	IC50	900	nM	CHEMBL2313636
6.00	IC50	1000	nM	CHEMBL3808606
6.00	IC50	1000	nM	CHEMBL3808989
5.96	IC50	1100	nM	CHEMBL3809399
5.96	IC50	1100	nM	CHEMBL3808484
5.92	IC50	1200	nM	CHEMBL1500419
5.92	IC50	1200	nM	CHEMBL4213611
5.92	IC50	1200	nM	CHEMBL5971809
5.89	IC50	1300	nM	CHEMBL2313645
5.89	IC50	1300	nM	CHEMBL3809121
5.85	IC50	1400	nM	CHEMBL3808689
5.82	IC50	1500	nM	CHEMBL3809943
5.80	IC50	1600	nM	CHEMBL3809058
5.77	IC50	1700	nM	CHEMBL1253920
5.77	IC50	1700	nM	CHEMBL3809313
5.77	IC50	1700	nM	CHEMBL3809465
5.75	IC50	1800	nM	CHEMBL3810082
5.75	IC50	1800	nM	CHEMBL3808996
5.75	IC50	1800	nM	CHEMBL3809991
5.75	IC50	1800	nM	CHEMBL3810034
5.72	IC50	1900	nM	CHEMBL2313658
5.72	IC50	1900	nM	CHEMBL5790518
5.70	IC50	2000	nM	CHEMBL3810304
5.66	IC50	2200	nM	CHEMBL3809695
5.66	IC50	2200	nM	CHEMBL5835245
5.66	IC50	2200	nM	CHEMBL5833600
5.66	IC50	2200	nM	CHEMBL5860351
5.66	IC50	2200	nM	CHEMBL5860815
5.64	IC50	2300	nM	CHEMBL5935587
5.64	IC50	2300	nM	CHEMBL5776442
5.62	IC50	2400	nM	CHEMBL2313652
5.60	IC50	2500	nM	CHEMBL4214692
5.60	IC50	2500	nM	CHEMBL4210825
5.60	IC50	2500	nM	CHEMBL5827204
5.60	IC50	2500	nM	CHEMBL5772475
5.57	IC50	2700	nM	CHEMBL3809067
5.54	IC50	2900	nM	CHEMBL3810341

PubChem BioAssay actives

72 with measured affinity, of 210 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
2,4-dimethyl-1-(2,4,6-trimethylphenyl)sulfonylpyrrole	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	0.3000	uM
2,4,6-trimethyl-N-(2,4,6-trimethylphenyl)aniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	0.4000	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	0.4000	uM
1,3,5-trimethyl-2-(4-methylphenyl)sulfonylbenzene	1138159: Inhibition of EPAC2 (unknown origin)	ic50	0.4000	uM
N-(2,5-dichlorophenyl)-2,4,6-trimethylaniline	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	0.4000	uM
N-[3-chloro-5-(trifluoromethyl)phenyl]-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	0.5000	uM
N-(3-chloro-2-methylphenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	0.5000	uM
2-ethyl-1-(2,4,6-trimethylphenyl)sulfonylpyrrole	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	0.5000	uM
N-[3,5-bis(trifluoromethyl)phenyl]-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	0.6000	uM
3-(3-methoxypropyl)-4-methyl-N-(2,4,6-trimethylphenyl)-1,3-thiazol-3-ium-2-amine iodide	1138159: Inhibition of EPAC2 (unknown origin)	ic50	0.6000	uM
N-(2,4-dichloro-6-methylphenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	0.7000	uM
1,3,5-trimethyl-2-(2,4,5-trimethylphenyl)sulfonylbenzene	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	0.7000	uM
N-(3,5-dichlorophenyl)-2,4,6-trimethylaniline	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	0.9000	uM
N-(2,3-dimethylphenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.0000	uM
2,4,6-trimethyl-N-(3,4,5-trichlorophenyl)aniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.1000	uM
N-(3,4-dichlorophenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.1000	uM
(1E)-N-(3,5-dichloroanilino)-2-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanimidoyl cyanide	1367372: Antagonist activity at recombinant full length EPAC2 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	1.2000	uM
1-(2,4,6-trimethylphenyl)sulfonylindole	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	1.2000	uM
1-(2,4-dimethylphenyl)sulfonyl-2-ethylpyrrole	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	1.3000	uM
N-(5-chloro-2-methylphenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.4000	uM
N-(3-bromophenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.5000	uM
N-(4-bromophenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.6000	uM
N-(3,5-dimethylphenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.7000	uM
5-[(2-hydroxynaphthalen-1-yl)diazenyl]naphthalene-2-sulfonic acid	1138158: Displacement of 8-NBD-cAMP from EPAC2 (unknown origin) by fluorescence plate reader analysis	ic50	1.7000	uM
N-(2,4,6-trimethylphenyl)-2,3-dihydro-1H-inden-5-amine	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.8000	uM
N-(3-ethylphenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.8000	uM
N-(3-chloro-4-methylphenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.8000	uM
N-(2,5-dimethylphenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	1.8000	uM
2-(4-methoxyphenyl)sulfonyl-1,3,5-trimethylbenzene	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	1.9000	uM
2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]aniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	2.0000	uM
N-(2,4-dimethylphenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	2.2000	uM
1-(2,4,6-trimethylphenyl)sulfonylpyrrolo[2,3-b]pyridine	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	2.4000	uM
(1E)-2-(4-tert-butylphenyl)-N-(3,5-dichloroanilino)-2-oxoethanimidoyl cyanide	1367372: Antagonist activity at recombinant full length EPAC2 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	2.5000	uM
(1E)-N-(3,5-dichloroanilino)-2-naphthalen-2-yl-2-oxoethanimidoyl cyanide	1367372: Antagonist activity at recombinant full length EPAC2 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	2.5000	uM
2,4,6-trimethyl-N-(2,4,6-trifluorophenyl)aniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	2.7000	uM
N-(3-chloro-4-fluorophenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	2.9000	uM
N-(3-chloro-5-fluorophenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	2.9000	uM
2,4,6-trimethyl-N-(3,4,5-trifluorophenyl)aniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	3.0000	uM
(1E)-2-(4-tert-butylphenyl)-2-oxo-N-(3,4,5-trichloroanilino)ethanimidoyl cyanide	1367372: Antagonist activity at recombinant full length EPAC2 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	3.0000	uM
N-(4-chloro-3-fluorophenyl)-2,4,6-trimethylaniline	1304077: Inhibition of 8-NBD-cAMP binding to EPAC2 (unknown origin) by microplate reader analysis	ic50	3.3000	uM
(1E)-2-(4-tert-butylphenyl)-N-(3-chloro-5-fluoroanilino)-2-oxoethanimidoyl cyanide	1367372: Antagonist activity at recombinant full length EPAC2 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	3.4000	uM
2,4,6-trimethyl-N-(4-methylphenyl)aniline	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	3.8000	uM
(E)-3-(3,4,5-trihydroxy-6-oxoxanthen-9-yl)prop-2-enoic acid	1138158: Displacement of 8-NBD-cAMP from EPAC2 (unknown origin) by fluorescence plate reader analysis	ic50	3.8000	uM
1-(2,4,6-trimethylphenyl)sulfonylpyrrolo[3,2-b]pyridine	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	3.8000	uM
4-cyclopropyl-2-[(2,5-dimethylphenyl)methylsulfanyl]-6-oxo-1H-pyrimidine-5-carbonitrile	663168: Competitive inhibition of Epac2 using fluorescent nucleotide analog 8-NBD-cAMP by fluorescence analysis	ic50	4.0000	uM
2-ethyl-1-(4-methylphenyl)sulfonylpyrrole	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	4.0000	uM
2-(4-iodophenyl)sulfonyl-1,3,5-trimethylbenzene	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	4.0000	uM
(1E)-2-(5-tert-butyl-1,2-oxazol-3-yl)-N-(3-chloroanilino)-2-oxoethanimidoyl cyanide	1235274: Antagonist activity at EPAC2 (unknown origin) assessed as cAMP-induced guanine nucleotide exchange factor activity	ic50	4.4000	uM
1-(3,5-dimethylphenyl)sulfonyl-2-ethylpyrrole	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	4.7000	uM
2-ethyl-1-(2-methylphenyl)sulfonylpyrrole	723507: Antagonist activity at recombinant EPAC2 (unknown origin) assessed 8-NBD-cAMP substrate fluorescence intensity by substrate competing assay	ic50	5.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, decreases expression	4
Aflatoxin B1	affects expression, decreases expression, increases methylation	3
Tobacco Smoke Pollution	affects cotreatment, affects reaction, increases response to substance, increases secretion, decreases expression	2
fluorene-9-bisphenol	increases expression	1
methylselenic acid	increases expression	1
senecionine	decreases expression	1
senkirkine	decreases expression	1
heliotrine	decreases expression	1
N-(1,3-dimethylbutyl)-N’-phenyl-1,4-phenylenediamine	affects response to substance	1
sodium arsenite	increases expression	1
ochratoxin A	increases expression	1
benzo(e)pyrene	decreases methylation	1
pentabromodiphenyl ether	increases expression	1
CGP 52608	increases reaction, affects binding	1
8-(4-chloro-phenylthio)-2’-O-methyladenosine-3’-5’-cyclic monophosphate	affects reaction, increases secretion, affects cotreatment, increases response to substance	1
abrine	decreases expression	1
asparanin A	decreases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Glyphosate	increases expression	1
Vehicle Emissions	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Clorgyline	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Methapyrilene	decreases methylation	1
Phthalic Acids	decreases methylation	1

ChEMBL screening assays

24 unique, capped per target: 22 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2033343	Binding	Inhibition of Epac2 at 25 uM in presence of equal molar concentration of cAMP	5-Cyano-6-oxo-1,6-dihydro-pyrimidines as potent antagonists targeting exchange proteins directly activated by cAMP. — Bioorg Med Chem Lett
CHEMBL3214906	Functional	PubChem BioAssay. qHTS for Agonist of cAMP-regulated guanine nucleotide exchange factor 4 (EPAC2): primary screen. (Class of assay: confirmatory)	PubChem BioAssay data set

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer