RAPGEF3

Summary

RAPGEF3 (Rap guanine nucleotide exchange factor 3, HGNC:16629) is a protein-coding gene on chromosome 12q13.11, encoding Rap guanine nucleotide exchange factor 3 (O95398). Guanine nucleotide exchange factor (GEF) for RAP1A and RAP2A small GTPases that is activated by binding cAMP.

Enables guanyl-nucleotide exchange factor activity and protein domain specific binding activity. Involved in several processes, including Rap protein signal transduction; cellular response to cAMP; and regulation of syncytium formation by plasma membrane fusion. Located in several cellular components, including filopodium; lamellipodium; and microvillus. Implicated in nicotine dependence. Biomarker of congestive heart failure.

Source: NCBI Gene 10411 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 164 total
• Druggable target: yes
• MANE Select transcript: NM_001098531

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16629
Approved symbol	RAPGEF3
Name	Rap guanine nucleotide exchange factor 3
Location	12q13.11
Locus type	gene with protein product
Status	Approved
Aliases	cAMP-GEFI, EPAC, bcm910
Ensembl gene	ENSG00000079337
Ensembl biotype	protein_coding
OMIM	606057
Entrez	10411

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 17 protein_coding, 8 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000389212, ENST00000395358, ENST00000395360, ENST00000405493, ENST00000449771, ENST00000466322, ENST00000473777, ENST00000476259, ENST00000479866, ENST00000482843, ENST00000488250, ENST00000490387, ENST00000494764, ENST00000495465, ENST00000495953, ENST00000547856, ENST00000548434, ENST00000548919, ENST00000549151, ENST00000549347, ENST00000868729, ENST00000868730, ENST00000868731, ENST00000868732, ENST00000868733, ENST00000868734, ENST00000963420, ENST00000963421, ENST00000963422

RefSeq mRNA: 3 — MANE Select: NM_001098531 NM_001098531, NM_001098532, NM_006105

CCDS: CCDS31784, CCDS41775

Canonical transcript exons

ENST00000449771 — 28 exons

Exon	Start	End
ENSE00003463305	47739143	47739230
ENSE00003472290	47750341	47750425
ENSE00003489036	47740915	47741040
ENSE00003489849	47748074	47748152
ENSE00003491586	47740642	47740823
ENSE00003493479	47751048	47751216
ENSE00003496470	47743530	47743676
ENSE00003504810	47749930	47749990
ENSE00003521169	47738193	47738247
ENSE00003524152	47738690	47738754
ENSE00003546388	47738022	47738093
ENSE00003556943	47747712	47747862
ENSE00003581532	47748819	47748931
ENSE00003581850	47743987	47744068
ENSE00003584344	47757866	47758078
ENSE00003594499	47751399	47751520
ENSE00003610717	47748454	47748542
ENSE00003614670	47749390	47749536
ENSE00003620754	47751723	47751829
ENSE00003623462	47751916	47751969
ENSE00003630280	47747544	47747626
ENSE00003633843	47740305	47740395
ENSE00003640119	47741505	47741602
ENSE00003646482	47740141	47740191
ENSE00003681689	47746860	47746899
ENSE00003685232	47749741	47749817
ENSE00003719068	47734363	47737685
ENSE00003846223	47758551	47758880

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 99.14.

FANTOM5 (CAGE): breadth broad, TPM avg 4.4373 / max 114.0597, expressed in 838 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130690	2.8767	697
130688	0.3616	162
130686	0.3109	170
130685	0.1934	118
130692	0.1587	65
130691	0.1374	60
130687	0.0966	51
130689	0.0840	58
130696	0.0754	21
130695	0.0613	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephros cortex	UBERON:0010533	99.14	gold quality
right lobe of thyroid gland	UBERON:0001119	97.84	gold quality
apex of heart	UBERON:0002098	97.62	gold quality
right ovary	UBERON:0002118	97.18	gold quality
left lobe of thyroid gland	UBERON:0001120	97.07	gold quality
left ovary	UBERON:0002119	97.01	gold quality
tendon of biceps brachii	UBERON:0008188	96.85	gold quality
right uterine tube	UBERON:0001302	96.72	gold quality
omental fat pad	UBERON:0010414	96.38	gold quality
thyroid gland	UBERON:0002046	96.35	gold quality
peritoneum	UBERON:0002358	96.30	gold quality
sural nerve	UBERON:0015488	96.12	gold quality
lower esophagus mucosa	UBERON:0035834	96.03	gold quality
endocervix	UBERON:0000458	95.97	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.62	gold quality
ectocervix	UBERON:0012249	94.93	gold quality
left uterine tube	UBERON:0001303	94.77	gold quality
amygdala	UBERON:0001876	94.55	gold quality
body of uterus	UBERON:0009853	94.30	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.27	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.17	gold quality
tibial nerve	UBERON:0001323	93.40	gold quality
putamen	UBERON:0001874	93.26	gold quality
mucosa of stomach	UBERON:0001199	93.18	gold quality
right frontal lobe	UBERON:0002810	93.07	gold quality
olfactory bulb	UBERON:0002264	92.97	silver quality
caudate nucleus	UBERON:0001873	92.64	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.56	gold quality
lower esophagus	UBERON:0013473	92.44	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	19.59
E-ANND-3	yes	12.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3, HIF1A

miRNA regulators (miRDB)

81 targeting RAPGEF3, 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-7110-3P	100.00	73.18	2486
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-3714	99.71	70.74	2671

Literature-anchored findings (GeneRIF, showing 40)

• role in regulating protein kinase B activity (PMID:11801596)
• the subcellular localization of Epac is cell cycle-dependent, it disassociates from the nuclear membrane and localizes to the mitotic spindle and centrosomes in metaphase so may play an important role in mitosis (PMID:12000763)
• the LID region plays a pivotal role in the communication between the regulatory and catalytic part of Epac (PMID:12707263)
• Epac signals to the JNK cascade through a new mechanism that does not involve its canonical catalytic action (PMID:12783872)
• results demonstrate that B-CLL cells uniquely activate Rap1 in response to PDE4 inhibitors and suggest that physiologic stimuli that activate EPAC may transmit an antiapoptotic signal (PMID:14615375)
• Epac-Rap signaling promotes cadherin-mediated cell-cell adhesions (PMID:15166221)
• a novel protein-binding partner for EPAC1 and EPAC2, light chain 2 of MAP1A (microtubule-associated protein 1A) (PMID:15202935)
• cAMP-Epac-Rap1 pathway regulates cell spreading and cell adhesion to laminin-5 through the alpha3beta1 integrin but not the alpha6beta4 integrin (PMID:15302884)
• Epac- and Ca2+ control activation of Ras and extracellular signal-regulated kinases by Gs-coupled receptors (PMID:15319437)
• Activation of Epac results in markedly enhanced basal endothelial barrier function by increasing cortical actin and subsequent redistribution of adherens and tight junctional molecules to cell-cell contacts (PMID:15374886)
• intracellular cAMP dynamics and Epac activation (PMID:15545605)
• MAP1A LC2 is a biological enhancer of EPAC1 activity toward Rap1 and associated downstream signaling mechanisms (PMID:15591041)
• cAMP-Epac-Rap1 signaling promotes decreased cell permeability by enhancing VE-cadherin-mediated adhesion lined by the rearranged cortical actin (PMID:15601837)
• Results suggest that in human umbilical vein endothelial cells Epac1 controls VE-cadherin-mediated cell junction formation and induces reorganization of the actin cytoskeleton. (PMID:16115630)
• Epac1 and cAMP-dependent protein kinase holoenzyme have similar cAMP affinity, but different cAMP domains (PMID:16728394)
• The Epac1-Rap1 pathway is present in both monocytes and macrophages, but only regulates specific immune effector functions in macrophages. (PMID:16751380)
• GPCRs rapidly activate R-Ras; R-Ras activation by the GPCRs is apparently directly induced by cyclic AMP-regulated Epac proteins; and activated R-Ras specifically controls GPCR-mediated phospholipase D stimulation (PMID:16754664)
• These results demonstrate that Epac plays an important role in connecting the microtubule cytoskeleton network and intracellular cAMP-signalling. (PMID:16880999)
• These data argue for the existence of a novel cAMP/Epac/Rap1/SOCS-3 pathway for limiting IL-6 receptor signaling in Endothelial Cells and illuminate a new mechanism by which cAMP may mediate its potent anti-inflammatory effects. (PMID:16914720)
• activation of Epac1, stimulation of cells with serotonin to induce cAMP production resulted in Rap1 activation, increased cell adhesion and polarization, and enhanced chemotaxis. (PMID:16940330)
• Rap1 mediates cyclic AMP-stimulated neurotensin secretion downstream of both Epac and protein kinase A signaling pathways (PMID:17068197)
• Epac1 inhibits TGFbeta-dependent regulation of cell migration and adhesion through TbetaRI (PMID:17203972)
• 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 activation in HUVEC results in ERK1/2 activation, and this protein, at least in part, mediates response to the physiologically relevant event of A(2B)AR stimulation (PMID:17565009)
• Epac increased ryanodine receptor phosphorylation at the CaMKII site. Reveal a new signalling pathway by which cAMP governs Ca(2+) release and signalling in cardiac myocytes. (PMID:17599964)
• Cells can contain several non-overlapping PKA- and EPAC-based signaling complexes that allow PDE4D/PDE3B coordination of cell adhesion. (PMID:17884339)
• Protein kinase A, not Epac, suppresses hedgehog activity and regulates glucocorticoid sensitivity in acute lymphoblastic leukemia cells (PMID:17895245)
• Evidence for involvement of EPAC or an EPAC-like cAMP effector protein in inhibition of human airwway smooth muscle proliferation. (PMID:17993585)
• These data demonstrate that activation of Epac1 increases integrin activity and integrin-dependent homing functions of progenitor cells. (PMID:18032709)
• These results suggest a novel mechanism of ANP protective effects against agonist-induced pulmonary endothelial cell barrier dysfunction via inhibition of Rho signaling by Epac/Rap1-Rac and PKA signaling cascades. (PMID:18064650)
• Epac1 was shown to be responsible for these actin changes and to colocalize with microtubules in human umbilical vein endothelial cells. (PMID:18172027)
• There exists in human beta-cells and rat INS-1 cells a novel form of ion channel modulation in which the ATP sensitivity of K(ATP) channels is regulated by Epac. (PMID:18202100)
• Epac1 is mainly expressed in human heart as compared with Epac2 isoform and is increased in heart failure (PMID:18323524)
• The selective use of PKA and Epac-1 pathways to inhibit distinct aspects of fibroblast activation illustrate the pleiotropic ability of PGE(2) to inhibit diverse fibroblast functions. (PMID:18421013)
• The regulation of Epac expression and activation thus appear to be critical for the integration of pro- and anti-fibrotic signals and for the regulation of fibroblast function. (PMID:18434542)
• 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)
• Suggest a role for cAMP/Epac1/Rap1 pathway in regulating proliferation of pancreatic carcinoma cells. (PMID:18580452)
• Epac1 rather than the classic cAMP effector PKA is a crucial element in the signal transduction pathway mediating anti-proliferative effects (PMID:18648773)
• The distribution of DNA-PK between nuclear and cytoplasmic compartments can thus potentially be influenced by relative inputs of cAMP signaling through the EPAC and PKA pathways. (PMID:18728186)
• the AC/cAMP/Epac signaling pathway in ovary may mediate the up-regulation of EGFR by gonadotropins via ERK1/2 and Akt activation (PMID:19022848)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rapgef3	ENSDARG00000079291
mus_musculus	Rapgef3	ENSMUSG00000022469
rattus_norvegicus	Rapgef3	ENSRNOG00000059961

Paralogs (24): RASGRF1 (ENSG00000058335), RASGRP2 (ENSG00000068831), RAPGEF4 (ENSG00000091428), 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 3 — O95398 (reviewed: O95398)

Alternative names: Exchange factor directly activated by cAMP 1, Exchange protein directly activated by cAMP 1, Rap1 guanine-nucleotide-exchange factor directly activated by cAMP, cAMP-regulated guanine nucleotide exchange factor I

All UniProt accessions (7): O95398, F8VRX1, F8VVJ6, F8VXK1, F8W0N0, H0YHS2, H0YIP6

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) for RAP1A and RAP2A small GTPases that is activated by binding cAMP. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which it activates the PI3K gamma complex and which is involved in angiogenesis. Plays a role in the modulation of the cAMP-induced dynamic control of endothelial barrier function through a pathway that is independent on Rho-mediated signaling. Required for the actin rearrangement at cell-cell junctions, such as stress fibers and junctional actin.

Subunit / interactions. Interacts with PDE3B and PIK3R6; form a signaling complex that regulates phosphatidylinositol 3-kinase gamma in angiogenesis.

Subcellular location. Endomembrane system.

Tissue specificity. Widely expressed with highest levels in adult kidney, heart, thyroid and brain, and fetal kidney.

Domain organisation. The DEP domain is involved in membrane localization independent from regulation by cAMP.

Isoforms (3)

UniProt ID	Names	Canonical?
O95398-1	1	yes
O95398-2	2
O95398-3	3

RefSeq proteins (3): NP_001092001, NP_001092002, NP_006096 (=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 (60 total): sequence conflict 12, strand 12, helix 9, mutagenesis site 8, sequence variant 4, domain 3, modified residue 3, splice variant 3, region of interest 2, binding site 2, chain 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6H7E	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95398-F1	77.81	0.46

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): 311–314; 321–322

Post-translational modifications (3): 864, 79, 528

Mutagenesis-validated functional residues (8):

Position	Phenotype
315	abolishes activation of rap1a.
321	reduces activation of rap1a.
342	diminishes gef activity dependence on camp concentration.
412	abolishes interaction with pde3b.
415	abolishes interaction with pde3b.
417	abolishes interaction with pde3b.
420	abolishes interaction with pde3b.
421	abolishes interaction with pde3b.

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: 0 (showing top):

GO Biological Process (23): angiogenesis (GO:0001525), adaptive immune response (GO:0002250), signal transduction (GO:0007165), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), Ras protein signal transduction (GO:0007265), associative learning (GO:0008306), positive regulation of insulin secretion (GO:0032024), Rap protein signal transduction (GO:0032486), regulation of actin cytoskeleton organization (GO:0032956), negative regulation of syncytium formation by plasma membrane fusion (GO:0034242), intracellular signal transduction (GO:0035556), positive regulation of GTPase activity (GO:0043547), regulation of angiogenesis (GO:0045765), positive regulation of angiogenesis (GO:0045766), positive regulation of protein export from nucleus (GO:0046827), positive regulation of stress fiber assembly (GO:0051496), regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051896), positive regulation of syncytium formation by plasma membrane fusion (GO:0060143), establishment of endothelial barrier (GO:0061028), cellular response to cAMP (GO:0071320), small GTPase-mediated signal transduction (GO:0007264), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), regulation of insulin secretion (GO:0050796)

GO Molecular Function (5): guanyl-nucleotide exchange factor activity (GO:0005085), protein domain specific binding (GO:0019904), cAMP binding (GO:0030552), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (8): plasma membrane (GO:0005886), microvillus (GO:0005902), endomembrane system (GO:0012505), membrane (GO:0016020), lamellipodium (GO:0030027), filopodium (GO:0030175), extracellular exosome (GO:0070062), cortical actin cytoskeleton (GO:0030864)

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
small GTPase-mediated signal transduction	2
syncytium formation by cell-cell fusion	2
regulation of syncytium formation by plasma membrane fusion	2
angiogenesis	2
actin-based cell projection	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
immune response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
learning	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
negative regulation of cellular component organization	1
intracellular anatomical structure	1
signal transduction	1
GTPase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
regulation of anatomical structure morphogenesis	1
regulation of vasculature development	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
protein export from nucleus	1
positive regulation of nucleocytoplasmic transport	1
regulation of protein export from nucleus	1
positive regulation of intracellular protein transport	1
positive regulation of actin filament bundle assembly	1
stress fiber assembly	1

Protein interactions and networks

STRING

1528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAPGEF3	MAPK7	Q13164	977
RAPGEF3	PRKACA	P17612	974
RAPGEF3	PRKACG	P22612	974
RAPGEF3	PRKACB	P22694	970
RAPGEF3	AKAP6	Q13023	965
RAPGEF3	AKAP1	Q92667	957
RAPGEF3	ALDH7A1	P49419	946
RAPGEF3	ARRB2	P32121	944
RAPGEF3	ARRB1	P49407	942
RAPGEF3	PDE4D	Q08499	910
RAPGEF3	LRPAP1	P30533	901
RAPGEF3	PDE4A	P27815	894
RAPGEF3	RAP2A	P10114	848
RAPGEF3	RAP1A	P10113	822
RAPGEF3	ADCY5	O95622	809

IntAct

16 interactions, top by confidence:

A	B	Type	Score
RAPGEF3	PDE3B	psi-mi:“MI:0915”(physical association)	0.640
PDE3B	RAPGEF3	psi-mi:“MI:0915”(physical association)	0.640
RAPGEF3	PDE3B	psi-mi:“MI:0407”(direct interaction)	0.640
PDE3B	RAPGEF3	psi-mi:“MI:0407”(direct interaction)	0.640
PDE3B	RAPGEF3	psi-mi:“MI:0914”(association)	0.640
PDE3B	RAPGEF3	psi-mi:“MI:0403”(colocalization)	0.640
RAPGEF3	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.440
	RAPGEF3	psi-mi:“MI:0915”(physical association)	0.400
RAPGEF3	PIK3R6	psi-mi:“MI:0915”(physical association)	0.400
RAPGEF3	RAP1B	psi-mi:“MI:0915”(physical association)	0.400
RAPGEF3		psi-mi:“MI:0914”(association)	0.350

BioGRID (23): RAPGEF3 (Two-hybrid), RAPGEF3 (Two-hybrid), RAPGEF3 (Reconstituted Complex), RAPGEF3 (Two-hybrid), RAPGEF3 (Two-hybrid), TGFB1 (Two-hybrid), DDX6 (Two-hybrid), EXOC8 (Two-hybrid), OARD1 (Two-hybrid), UFSP1 (Two-hybrid), RAP2A (Biochemical Activity), RAP1A (Biochemical Activity), RAPGEF3 (Affinity Capture-RNA), RAPGEF3 (Affinity Capture-MS), RAPGEF3 (Affinity Capture-Western)

ESM2 similar proteins: A0A140LI67, B5KFD7, D4A7V9, M0R4F8, O08774, O35827, O43187, O70167, O70173, O88866, O88900, O95398, O95704, P0C5Y8, Q0P5I2, Q13322, Q14449, Q4QQS0, Q5BIW4, Q5ICW4, Q5JV73, Q5PQS0, Q5R810, Q60760, Q68DX3, Q6IFT4, Q6IRN0, Q6P4K6, Q6REY9, Q6S5L8, Q6TXD4, Q7TSI1, Q80TQ5, Q80VA5, Q8BW88, Q8CFA1, Q8IWE5, Q8R1C9, Q8R2S1, Q8VCC8

Diamond homologs: A0JM95, A4IFE4, F1M386, F1MSG6, F1PBJ0, O95398, P28818, P83900, Q02342, Q0VAM2, Q28EC1, Q5RC04, Q6DBW1, Q6DHR3, Q8C0Q9, Q8CHG7, Q8IS19, Q8JZL7, Q8MVR1, Q8N431, Q8N9B8, Q8VCC8, Q8WZA2, Q92565, Q95KH6, Q9D300, Q9EQZ6, Q9UHV5, Q9Y4G8, Q9Z1C7, Q9Z1C8, A2AR50, A4IJ06, A6N9I4, A8XQD5, A8XWC4, G5EDB9, O14795, O45818, O54874

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GRK2	“down-regulates activity”	RAPGEF3	phosphorylation
RAPGEF3	“up-regulates activity”	RAP1A	“guanine nucleotide exchange factor”
RAPGEF3	“up-regulates activity”	RAP1B	“guanine nucleotide exchange factor”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	123
Likely benign	8
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

4703 predictions. Top by Δscore:

Variant	Effect	Δscore
12:47737686:C:CC	acceptor_gain	1.0000
12:47738018:TTA:T	donor_loss	1.0000
12:47738019:TAC:T	donor_loss	1.0000
12:47738020:A:AC	donor_gain	1.0000
12:47738020:ACA:A	donor_loss	1.0000
12:47738021:C:CG	donor_gain	1.0000
12:47738021:CA:C	donor_gain	1.0000
12:47738021:CAT:C	donor_gain	1.0000
12:47738021:CATG:C	donor_gain	1.0000
12:47738021:CATGT:C	donor_gain	1.0000
12:47738089:AGGCA:A	acceptor_gain	1.0000
12:47738090:GGCA:G	acceptor_gain	1.0000
12:47738091:GCA:G	acceptor_gain	1.0000
12:47738092:CA:C	acceptor_gain	1.0000
12:47738092:CAC:C	acceptor_gain	1.0000
12:47738093:ACT:A	acceptor_loss	1.0000
12:47738094:C:CC	acceptor_gain	1.0000
12:47738094:CT:C	acceptor_loss	1.0000
12:47738095:T:C	acceptor_loss	1.0000
12:47738102:G:GC	acceptor_gain	1.0000
12:47738246:CT:C	acceptor_gain	1.0000
12:47738248:C:CC	acceptor_gain	1.0000
12:47738684:ACTCA:A	donor_loss	1.0000
12:47738685:CTCA:C	donor_loss	1.0000
12:47738686:TCACC:T	donor_loss	1.0000
12:47738687:CACCA:C	donor_loss	1.0000
12:47738688:A:AC	donor_gain	1.0000
12:47738688:A:C	donor_loss	1.0000
12:47738689:C:A	donor_loss	1.0000
12:47738689:C:CC	donor_gain	1.0000

AlphaMissense

5998 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:47739145:T:A	K820I	0.999
12:47749499:C:T	G311E	0.999
12:47749763:A:T	V291D	0.999
12:47749788:A:G	W283R	0.999
12:47749788:A:T	W283R	0.999
12:47740360:G:T	A756D	0.998
12:47749427:A:G	L335P	0.998
12:47749457:A:T	I325N	0.998
12:47749463:G:T	A323D	0.998
12:47749487:A:G	L315P	0.998
12:47749500:C:G	G311R	0.998
12:47749500:C:T	G311R	0.998
12:47749501:A:C	F310L	0.998
12:47749501:A:T	F310L	0.998
12:47749502:A:G	F310S	0.998
12:47749503:A:G	F310L	0.998
12:47749813:G:C	F274L	0.998
12:47749813:G:T	F274L	0.998
12:47749815:A:G	F274L	0.998
12:47739144:T:A	K820N	0.997
12:47739144:T:G	K820N	0.997
12:47740377:A:C	N750K	0.997
12:47740377:A:T	N750K	0.997
12:47740393:A:G	L745P	0.997
12:47749430:A:G	F334S	0.997
12:47749457:A:C	I325S	0.997
12:47749464:C:G	A323P	0.997
12:47749490:G:T	A314D	0.997
12:47749499:C:A	G311V	0.997
12:47749770:C:G	G289R	0.997

dbSNP variants (sampled 300 via entrez): RS1000028826 (12:47736483 G>A,C,T), RS1000170554 (12:47752088 G>A), RS1000179536 (12:47755691 T>A,C,G), RS1000492508 (12:47742343 C>T), RS1000532101 (12:47758220 G>A,C,T), RS1000665818 (12:47752450 T>C), RS1000666736 (12:47746641 G>A), RS1001023889 (12:47735437 C>T), RS1001025997 (12:47735235 G>A,T), RS1001256003 (12:47744066 G>A), RS1001489471 (12:47735676 C>T), RS1001721665 (12:47737628 T>C), RS1001784477 (12:47750897 C>A,T), RS1001788637 (12:47749117 C>A,G,T), RS1001842466 (12:47753465 C>G)

Disease associations

OMIM: gene MIM:606057 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST007483_45	Waist-to-hip ratio adjusted for BMI (additive genetic model)	7.000000e-17
GCST007487_10	Waist-to-hip ratio adjusted for BMI (additive genetic model)	5.000000e-16
GCST007500_13	Waist-to-hip ratio adjusted for BMI (additive genetic model)	1.000000e-14
GCST007502_8	Waist-to-hip ratio adjusted for BMI (additive genetic model)	1.000000e-14
GCST007611_20	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	7.000000e-11
GCST008103_172	Bipolar disorder	7.000000e-06
GCST008129_58	Body mass index	2.000000e-15
GCST90002401_238	Platelet distribution width	2.000000e-14
GCST90020024_266	A body shape index	1.000000e-11
GCST90020025_23	Waist-to-hip ratio adjusted for BMI	8.000000e-17
GCST90020027_1702	Waist-hip index	5.000000e-18
GCST90020029_447	Waist circumference adjusted for body mass index	5.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004340	body mass index
EFO:0007984	platelet component distribution width
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2029197 (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 (1 total), top 1:

Ligand	Action	Affinity	Parameter
ESI-09	Inhibition	5.49	pIC50

ChEMBL bioactivities

84 potent at pChembl≥5 of 142 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.28	EC50	530	nM	CHEMBL4549036
6.05	IC50	900	nM	CHEMBL4517829
5.96	EC50	1090	nM	CHEMBL1256796
5.66	EC50	2200	nM	CHEMBL397985
5.66	IC50	2200	nM	CHEMBL4576925
5.62	IC50	2400	nM	CHEMBL3593329
5.62	IC50	2400	nM	CHEMBL3593342
5.62	IC50	2400	nM	CHEMBL4103080
5.62	IC50	2400	nM	CHEMBL5935587
5.59	EC50	2540	nM	CHEMBL4442766
5.58	IC50	2600	nM	CHEMBL3593468
5.57	IC50	2700	nM	CHEMBL4099528
5.57	IC50	2700	nM	CHEMBL3593342
5.57	IC50	2700	nM	CHEMBL5790518
5.56	EC50	2750	nM	CHEMBL4468490
5.52	IC50	3000	nM	CHEMBL4081514
5.52	IC50	3000	nM	CHEMBL5860815
5.50	IC50	3200	nM	CHEMBL3260990
5.48	IC50	3300	nM	CHEMBL4171480
5.44	IC50	3600	nM	CHEMBL4100650
5.44	IC50	3600	nM	CHEMBL4213611
5.44	IC50	3600	nM	CHEMBL5833600
5.44	IC50	3600	nM	CHEMBL5971809
5.40	IC50	4000	nM	CHEMBL3593471
5.39	IC50	4100	nM	CHEMBL3593470
5.38	IC50	4200	nM	CHEMBL4082655
5.38	IC50	4200	nM	CHEMBL4171480
5.38	IC50	4200	nM	CHEMBL5776442
5.37	IC50	4300	nM	CHEMBL3593341
5.35	Kd	4500	nM	CYCLIC ADENOSINE MONOPHOSPHATE
5.34	IC50	4600	nM	CHEMBL4091792
5.34	IC50	4600	nM	CHEMBL4459738
5.34	IC50	4600	nM	CHEMBL5860351
5.32	IC50	4800	nM	CHEMBL4450888
5.31	Kd	4900	nM	CHEMBL4534834
5.30	EC50	5000	nM	CHEMBL4576925
5.30	EC50	5000	nM	CHEMBL4517829
5.30	EC50	5000	nM	CHEMBL4450888
5.29	IC50	5100	nM	CHEMBL5745765
5.27	IC50	5400	nM	CHEMBL4210825
5.27	IC50	5400	nM	CHEMBL5827204
5.26	IC50	5500	nM	CHEMBL4171480
5.26	IC50	5500	nM	CHEMBL4205201
5.26	IC50	5500	nM	CHEMBL6027015
5.25	IC50	5600	nM	CHEMBL4092921
5.25	IC50	5600	nM	CHEMBL4063555
5.25	IC50	5600	nM	CHEMBL4217436
5.25	EC50	5620	nM	CHEMBL1363683
5.25	IC50	5600	nM	CHEMBL5769664
5.25	IC50	5600	nM	CHEMBL6000491

PubChem BioAssay actives

60 with measured affinity, of 274 total; 48 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
sodium (4aR,6R,7R,7aS)-6-(4-amino-6-bromopyrrolo[2,3-d]pyrimidin-7-yl)-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol	1603251: Inhibition of 8Fluo-cAMP binding to recombinant human His-tagged EPAC1 (157 to 881 residues) expressed in Escherichia coli measured after 5 mins by fluorescence polarization assay	ec50	0.5300	uM
N-(4-amino-2-methoxyphenyl)sulfonyl-2-(7-methoxynaphthalen-2-yl)oxyacetamide	1549077: Binding affinity to GST-tagged recombinant EPAC1 CNBD (169 to 318 residues) (unknown origin) expressed in Escherichia coli BL21 Star (DE3) incubated for 4 hrs by 8-NBD-cAMP competition binding assay	ic50	0.9000	uM
sodium (4aR,6R,7R,7aS)-6-(6-amino-8-bromopurin-9-yl)-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol	1603251: Inhibition of 8Fluo-cAMP binding to recombinant human His-tagged EPAC1 (157 to 881 residues) expressed in Escherichia coli measured after 5 mins by fluorescence polarization assay	ec50	1.0900	uM
2-(7-methoxynaphthalen-2-yl)oxy-N-naphthalen-2-ylsulfonylacetamide	1549077: Binding affinity to GST-tagged recombinant EPAC1 CNBD (169 to 318 residues) (unknown origin) expressed in Escherichia coli BL21 Star (DE3) incubated for 4 hrs by 8-NBD-cAMP competition binding assay	ic50	2.2000	uM
9-[(4aR,6R,7R,7aR)-2-hydroxy-7-methoxy-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-6-yl]-8-(4-chlorophenyl)sulfanylpurin-6-amine	1364435: Activation of EPAC1 DEP1 deletion mutant (unknown origin) expressed in mouse NIH-3T3-A14 cells assessed as increase in Rap1b- fluorescent nucleotide methylontraniloyl-GDP nucleotide exchange by fluorescence assay	ec50	2.2000	uM
(1E)-2-(5-tert-butyl-1,2-oxazol-3-yl)-2-oxo-N-(3,4,5-trichloroanilino)ethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	2.4000	uM
(1E)-N-[4-chloro-3-(trifluoromethyl)anilino]-2-oxo-2-(5-phenyl-1,2-oxazol-3-yl)ethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	2.4000	uM
(1E)-2-(5-tert-butyl-1,2-oxazol-3-yl)-N-(3,5-dichloroanilino)-2-oxoethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	2.4000	uM
sodium (4aR,6R,7R,7aS)-6-(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol	1603251: Inhibition of 8Fluo-cAMP binding to recombinant human His-tagged EPAC1 (157 to 881 residues) expressed in Escherichia coli measured after 5 mins by fluorescence polarization assay	ec50	2.5400	uM
(1E)-2-(5-cyclohexyl-1,2-oxazol-3-yl)-N-(3,5-dichloroanilino)-2-oxoethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	2.6000	uM
(1E)-2-(1,2-benzoxazol-3-yl)-N-[4-chloro-3-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	2.7000	uM
sodium (4aR,6R,7R,7aS)-6-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol	1603251: Inhibition of 8Fluo-cAMP binding to recombinant human His-tagged EPAC1 (157 to 881 residues) expressed in Escherichia coli measured after 5 mins by fluorescence polarization assay	ec50	2.7500	uM
(1E)-2-(1,2-benzoxazol-3-yl)-N-[3-chloro-4-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	3.0000	uM
(1E)-2-(5-tert-butyl-1,2-oxazol-3-yl)-N-(3-chloroanilino)-2-oxoethanimidoyl cyanide	1138160: Inhibition of EPAC1 (unknown origin) assessed as cAMP-mediated GEF activity	ic50	3.2000	uM
(2R)-5,7-dibromo-6-fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-carbaldehyde	1505265: Inhibition of recombinant human GST-tagged EPAC1 (149 to 881 residues) expressed in Escherichia coli Rosetta 2(DE3) assessed as reduction in guanine nucleotide exchange activity using BODIPY-labeled GDP loaded Rap1A by fluorescence assay	ic50	3.3000	uM
(1E)-N-(3,5-dichloroanilino)-2-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanimidoyl cyanide	1367371: Antagonist activity at recombinant full length EPAC1 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	3.6000	uM
(1E)-N-[3-chloro-5-(trifluoromethyl)anilino]-2-[5-(furan-2-yl)-1,2-oxazol-3-yl]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	3.6000	uM
(1E)-2-(5-cyclohexyl-1,2-oxazol-3-yl)-2-oxo-N-(3,4,5-trichloroanilino)ethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	4.0000	uM
(1E)-2-(5-cyclopropyl-1,2-oxazol-3-yl)-2-oxo-N-(3,4,5-trichloroanilino)ethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	4.1000	uM
(1E)-N-[4-chloro-3-(trifluoromethyl)anilino]-2-[5-(furan-2-yl)-1,2-oxazol-3-yl]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	4.2000	uM
(1E)-2-(5-tert-butyl-1,2-oxazol-3-yl)-N-[3-chloro-4-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	4.3000	uM
(4aR,6R,7R,7aS)-6-(6-aminopurin-9-yl)-2-hydroxy-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol	1649089: Binding affinity to GST-tagged human EPAC1 CNBD (149 to 318 residues) expressed in Escherichia coli BL21 (DE3) incubated for 30 mins by 8-NBD-cAMP based competitive fluorescence assay	kd	4.5000	uM
(1E)-2-(1,2-benzoxazol-3-yl)-N-[3-chloro-5-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	4.6000	uM
N-[3-methyl-5-[[3-(trifluoromethyl)-2-pyridinyl]amino]phenyl]sulfonyl-2-naphthalen-2-yloxyacetamide	1549077: Binding affinity to GST-tagged recombinant EPAC1 CNBD (169 to 318 residues) (unknown origin) expressed in Escherichia coli BL21 Star (DE3) incubated for 4 hrs by 8-NBD-cAMP competition binding assay	ic50	4.6000	uM
N-(2,4-dimethoxyphenyl)sulfonyl-2-naphthalen-2-yloxyacetamide	1549077: Binding affinity to GST-tagged recombinant EPAC1 CNBD (169 to 318 residues) (unknown origin) expressed in Escherichia coli BL21 Star (DE3) incubated for 4 hrs by 8-NBD-cAMP competition binding assay	ic50	4.8000	uM
N-(2,4-dimethylphenyl)sulfonyl-2-naphthalen-2-yloxyacetamide	1649090: Binding affinity to GST-tagged human EPAC1 L273W mutant expressed in Escherichia coli BL21 (DE3) incubated for 30 mins by 8-NBD-cAMP based competitive fluorescence assay	kd	4.9000	uM
(1E)-2-(4-tert-butylphenyl)-N-(3,5-dichloroanilino)-2-oxoethanimidoyl cyanide	1367371: Antagonist activity at recombinant full length EPAC1 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	5.4000	uM
(1E)-N-[3,5-bis(trifluoromethyl)anilino]-2-(4-tert-butylphenyl)-2-oxoethanimidoyl cyanide	1367371: Antagonist activity at recombinant full length EPAC1 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	5.5000	uM
(1E)-2-(4-tert-butylphenyl)-N-[3-chloro-5-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1367371: Antagonist activity at recombinant full length EPAC1 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	5.6000	uM
(1E)-N-[4-chloro-3-(trifluoromethyl)anilino]-2-[5-(4-methoxyphenyl)-1,2-oxazol-3-yl]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	5.6000	uM
(1E)-N-[3,5-bis(trifluoromethyl)anilino]-2-[5-(4-methoxyphenyl)-1,2-oxazol-3-yl]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	5.6000	uM
sodium (4aR,6R,7R,7aS)-6-(6-aminopurin-9-yl)-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol	1603251: Inhibition of 8Fluo-cAMP binding to recombinant human His-tagged EPAC1 (157 to 881 residues) expressed in Escherichia coli measured after 5 mins by fluorescence polarization assay	ec50	5.6200	uM
(1E)-2-(5-tert-butyl-1,2-oxazol-3-yl)-N-[3-chloro-5-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	5.7000	uM
(1E)-N-[3,5-bis(trifluoromethyl)anilino]-2-(5-tert-butyl-1,2-oxazol-3-yl)-2-oxoethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	5.7000	uM
(1E)-2-(4-tert-butylphenyl)-N-[4-chloro-3-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1367371: Antagonist activity at recombinant full length EPAC1 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	6.1000	uM
(1E)-2-(4-tert-butylphenyl)-N-(3-chloro-5-fluoroanilino)-2-oxoethanimidoyl cyanide	1367371: Antagonist activity at recombinant full length EPAC1 (unknown origin) assessed as inhibition of cAMP-mediated Rap1b-BODIPY GDP nucleotide exchange activity	ic50	6.4000	uM
(1E)-2-(1,2-benzoxazol-3-yl)-N-[3,5-bis(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	6.7000	uM
(1E)-N-[3,5-bis(trifluoromethyl)anilino]-2-oxo-2-(5-phenyl-1,2-oxazol-3-yl)ethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	7.2000	uM
(1E)-2-[5-(4-tert-butylphenyl)-1,2-oxazol-3-yl]-N-[4-chloro-3-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	7.3000	uM
(1E)-2-(5-tert-butyl-1,2-oxazol-3-yl)-N-(3-chloro-4-fluoroanilino)-2-oxoethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	7.8000	uM
(1E)-2-[5-(4-chlorophenyl)-1,2-oxazol-3-yl]-N-[4-chloro-3-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	7.8000	uM
(1E)-2-(1,2-benzoxazol-3-yl)-N-(3-chloro-4-fluoroanilino)-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	8.5000	uM
(1E)-2-[5-(4-tert-butylphenyl)-1,2-oxazol-3-yl]-N-(3-chloroanilino)-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	8.6000	uM
(1E)-2-(5-tert-butyl-1,2-oxazol-3-yl)-2-oxo-N-(3,4,5-trifluoroanilino)ethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	8.9000	uM
(1E)-2-[5-(4-tert-butylphenyl)-1,2-oxazol-3-yl]-N-[3-chloro-4-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	9.0000	uM
(1E)-N-[3-chloro-5-(trifluoromethyl)anilino]-2-oxo-2-(5-phenyl-1,2-oxazol-3-yl)ethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	9.5000	uM
(1E)-2-(5-tert-butyl-1,2-oxazol-3-yl)-N-[4-chloro-3-(trifluoromethyl)anilino]-2-oxoethanimidoyl cyanide	1235279: Antagonist activity at human recombinant EPAC1 assessed as inhibition of Rap1b-bGDP exchange activity	ic50	9.7000	uM
(1E)-N-(3-chloroanilino)-2-[5-(furan-2-yl)-1,2-oxazol-3-yl]-2-oxoethanimidoyl cyanide	1466101: Antagonist activity at recombinant human full length EPAC1 assessed as inhibition of EPAC1-mediated Rap1B (1 to 167 residues)-BODIPY GDP nucleotide exchange activity by 8-NBD-cAMP competition assay	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases expression, increases methylation, increases reaction, increases transport (+2 more)	4
Ethinyl Estradiol	affects expression, decreases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression, increases methylation, affects cotreatment, affects reaction (+2 more)	3
Aflatoxin B1	increases expression, increases methylation	3
bisphenol A	affects expression	2
8-(4-chloro-phenylthio)-2’-O-methyladenosine-3’-5’-cyclic monophosphate	increases cleavage, affects cotreatment, increases response to substance, increases secretion, affects reaction (+2 more)	2
Vehicle Emissions	decreases expression, decreases reaction	2
Cisplatin	decreases reaction, increases activity, increases cleavage, affects cotreatment, increases expression (+1 more)	2
Nickel	decreases expression	2
Particulate Matter	decreases expression, decreases reaction, increases expression	2
bisphenol F	affects cotreatment, increases methylation	1
beta-lapachone	increases expression	1
aflatoxin B2	increases methylation	1
CGP 52608	increases reaction, affects binding	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Calcium	increases reaction, increases transport	1
Diethylhexyl Phthalate	decreases expression	1
Diethylnitrosamine	increases expression	1
Estradiol	decreases expression	1
Hydrocortisone	increases expression, decreases reaction	1
Levodopa	increases expression	1
Triclosan	increases expression	1
Tunicamycin	increases expression	1
Valproic Acid	increases methylation	1
Mifepristone	increases expression, decreases reaction	1
Okadaic Acid	increases expression	1
Genistein	affects expression	1

ChEMBL screening assays

71 unique, capped per target: 69 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2033342	Binding	Inhibition of Epac1 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
CHEMBL3214967	Functional	PubChem BioAssay. qHTS for Antagonist of cAMP-regulated guanine nucleotide exchange factor 3 (EPAC1): primary screen. (Class of assay: confirmatory)	PubChem BioAssay data set

Clinical trials (associated diseases)

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