EPAS1

Summary

EPAS1 (endothelial PAS domain protein 1, HGNC:3374) is a protein-coding gene on chromosome 2p21, encoding Endothelial PAS domain-containing protein 1 (Q99814). Transcription factor involved in the induction of oxygen regulated genes. In precision oncology, EPAS1 Overexpression confers sensitivity to Belzutifan in Von Hippel-Lindau Disease (CIViC Level B); 1 further curated variant–drug associations are listed below.

This gene encodes a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall. The encoded protein contains a basic-helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. Mutations in this gene are associated with erythrocytosis familial type 4.

Source: NCBI Gene 2034 — RefSeq curated summary.

At a glance

• Gene–disease (curated): erythrocytosis, familial, 4 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 36
• Clinical variants (ClinVar): 1,825 total — 4 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 45
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Transcription factor: yes — 100 downstream targets (CollecTRI)
• MANE Select transcript: NM_001430

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3374
Approved symbol	EPAS1
Name	endothelial PAS domain protein 1
Location	2p21
Locus type	gene with protein product
Status	Approved
Aliases	MOP2, PASD2, HIF2A, HLF, bHLHe73
Ensembl gene	ENSG00000116016
Ensembl biotype	protein_coding
OMIM	603349
Entrez	2034

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 7 protein_coding, 4 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000263734, ENST00000449347, ENST00000460015, ENST00000463191, ENST00000465318, ENST00000466465, ENST00000467888, ENST00000468530, ENST00000475822, ENST00000483692, ENST00000861816, ENST00000861817, ENST00000861818, ENST00000861819, ENST00000861820

RefSeq mRNA: 1 — MANE Select: NM_001430 NM_001430

CCDS: CCDS1825

Canonical transcript exons

ENST00000263734 — 16 exons

Exon	Start	End
ENSE00000751537	46356151	46356302
ENSE00000751546	46369827	46369933
ENSE00000962618	46375690	46375837
ENSE00000962620	46378657	46378767
ENSE00000962621	46380227	46380717
ENSE00001816384	46384509	46386697
ENSE00001875413	46297407	46297937
ENSE00003488845	46382425	46382598
ENSE00003503490	46381596	46381722
ENSE00003528673	46377894	46378087
ENSE00003552182	46360638	46360756
ENSE00003556558	46346873	46347063
ENSE00003569429	46381975	46382089
ENSE00003649720	46376539	46376753
ENSE00003683801	46356724	46356808
ENSE00003784699	46360885	46361090

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 166.7868 / max 4351.6804, expressed in 1738 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20062	153.9694	1714
20065	5.5170	950
20060	1.5095	982
20064	1.4109	620
20061	1.0095	716
20082	0.9069	447
20073	0.6959	425
20072	0.5572	335
20066	0.4682	258
20063	0.3797	195

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	99.85	gold quality
lower lobe of lung	UBERON:0008949	99.84	gold quality
adult organism	UBERON:0007023	99.76	gold quality
nasal cavity epithelium	UBERON:0005384	99.75	gold quality
blood vessel layer	UBERON:0004797	99.71	gold quality
placenta	UBERON:0001987	99.69	gold quality
visceral pleura	UBERON:0002401	99.68	gold quality
upper lobe of lung	UBERON:0008948	99.62	gold quality
upper lobe of left lung	UBERON:0008952	99.60	gold quality
nasal cavity mucosa	UBERON:0001826	99.59	gold quality
saphenous vein	UBERON:0007318	99.58	gold quality
superficial temporal artery	UBERON:0001614	99.56	gold quality
pericardium	UBERON:0002407	99.54	gold quality
vena cava	UBERON:0004087	99.53	gold quality
pleura	UBERON:0000977	99.35	gold quality
right coronary artery	UBERON:0001625	99.34	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.34	gold quality
lung	UBERON:0002048	99.31	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.29	gold quality
inferior olivary complex	UBERON:0002127	99.27	gold quality
choroid plexus epithelium	UBERON:0003911	99.26	gold quality
bronchial epithelial cell	CL:0002328	99.24	gold quality
heart right ventricle	UBERON:0002080	99.23	gold quality
parietal pleura	UBERON:0002400	99.22	gold quality
coronary artery	UBERON:0001621	99.21	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.20	gold quality
urethra	UBERON:0000057	99.18	gold quality
left coronary artery	UBERON:0001626	99.18	gold quality
popliteal artery	UBERON:0002250	99.18	gold quality
tibial artery	UBERON:0007610	99.17	gold quality

Single-cell (SCXA)

Detected in 36 experiment(s), a significant marker in 34.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	3753.56
E-ANND-2	yes	3466.95
E-HCAD-15	yes	3459.99
E-GEOD-131882	yes	3456.57
E-MTAB-6308	yes	2857.48
E-MTAB-6653	yes	2622.04
E-CURD-119	yes	2498.59
E-GEOD-130148	yes	2215.71
E-GEOD-135922	yes	2119.78
E-HCAD-35	yes	1567.32
E-GEOD-180759	yes	1180.07
E-CURD-114	yes	590.35
E-GEOD-81383	yes	77.80
E-MTAB-10287	yes	76.86
E-HCAD-1	yes	61.90

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

100 targets.

Target	Regulation
ADM	Activation
ADORA2A	Unknown
AHR	Repression
AKT1
BHLHE40	Unknown
BMAL1	Unknown
BNIP3	Repression
CA9	Activation
CACNA1A	Activation
CCR7	Activation
CDH5
CDKN1B	Activation
CITED2
COL10A1	Activation
CSF1R
CTCF
CXCL8	Activation
CYP51A1
DBH	Unknown
DDC
EFNA1
EGF
EGLN1
EGLN3	Unknown
EIF3E
ENO1	Unknown
EP300
EPAS1
EPO	Unknown
F12

JASPAR motifs

Motif	Name	Family
MA2325.1	EPAS1	PAS domain factors

JASPAR matrix evidence (PMIDs): PMID:15039136

Upstream regulators (CollecTRI, top): ATF3, E2F4, EPAS1, HIF1A, HIF3A, HOXA1, RELA, SP1, SP3, STAT3, USF2, YY1

miRNA regulators (miRDB)

136 targeting EPAS1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-374A-5P	99.90	71.34	2923

Literature-anchored findings (GeneRIF, showing 40)

• hypoxic induction of the COOH-terminal transactivation domain (CAD)occurs through abrogation of hydroxylation of a conserved asparagine in the CAD (PMID:11823643)
• enzymatic hydroxylation of a conserved prolyl residue in hypoxia-inducible factor alpha subunits governs capture by the pVHL E3 ubiquitin ligase complex (PMID:12123724)
• expression related to increased angiogenesis in endometrial adenocarcinoma (PMID:12209691)
• HIF-2alpha and Ets-1 binding is required for transcriptional activation of Flk-1 in endothelial cells (PMID:12464608)
• MAPK signaling facilitates HIF1a and HIF2a activation through p300/CBP (PMID:12588875)
• HIF-2alpha regulates glyceraldehyde-3-phosphate dehydrogenase gene expression in vascular endothelial cells. (PMID:12697324)
• HIF2A is upregulated in rheumatoid arthritis and osteoarthritis. (PMID:12823854)
• Hypoxia-inducible factors 1alpha and 2alpha have roles in vascular endothelial growth factor expression and in nodular malignant melanomas of the skin (PMID:14512791)
• hypoxic gene induction in cells expressing HIF-2alpha but not HIF-1alpha (PMID:14645546)
• HIF-2alpha PAS-B binds the analogous ARNT domain in vitro (PMID:14668441)
• HIF2alpha has a role in regulating pVHL-defective tumor growth (PMID:14691554)
• trans-regulation between HIF-1alpha and HIF-2alpha during hypoxia likely conveys target gene specificity (PMID:14744852)
• HIF-2alpha/EPAS1 is expressed in most of hepatocellular carcinoma with capsular infiltration and portal vein invasion, which indicates a possible role of HIF-2alpha/EPAS1 in HCC (PMID:14966910)
• deregulation of hypoxia-inducible genes in VHL-/- cells can be attributed mainly to deregulation of HIF and validate HIF as a therapeutic anticancer drug target (PMID:14985465)
• role of EPAS1 and Sp1 in the hypoxic response of cancer cells (PMID:15039136)
• siRNA targeted degradation of HIF-1alpha and HIF-2alpha results in decreased hypoxia-induced PHD3 expression (PMID:15156561)
• EPAS1 may contribute to the construction of mature vessels by modulating the coordinated expressions of VEGF, Flt-1, Flk-1, and Tie2. (PMID:15192019)
• HIF-1alpha and HIF-2alpha in renal cell carcinoma harboring VHL mutations do not have a major role in radiosensitivity (PMID:15217953)
• the complete EPO enhancer displayed dependency on HIF-2alpha regulation, indicating that additional cis-acting elements confer HIF-2alpha specificity within this region (PMID:15240563)
• HIF1a and HIF2a are regulated by PHD1, PHD2, and PHD3 (PMID:15247232)
• The HIF2A is a transcription factor that plays a key role in the response of cells to oxygen levels. (PMID:15598469)
• HIF-2alpha protein is selectively present in human fetal week 8.5 SNS paraganglia. HIF-2alpha was detected in hypoxic and in well-oxygenized neuroblastoma cells and tissue, presumably reflecting their embryonic features. (PMID:15652356)
• Results describe the specific interaction of hypoxia-inducible factors (HIF)-2alpha, but not HIF-1alpha, with the NF-kappaB essential modulator (NEMO). (PMID:15653678)
• Enhanced expression of HIF2A suppressed HIF1A and vice-versa. (PMID:15964822)
• Overexpression of HIF-2alpha in glioma tumors enhances angiogenesis but reduces growth of these tumors, in part by increasing tumor cell apoptosis. (PMID:16098466)
• DNA variants in EPAS1 influence the relative contribution of aerobic and anaerobic metabolism and hence the maximum sustainable metabolic power for a given event duration (PMID:16208515)
• The role of HIF-1alpha and HIF-2alpha on cell migration and proliferation in fibroblasts during hypoxia is reported. (PMID:16263938)
• androgen receptor is involved in VEGF and hypoxia sensing via hypoxia-inducible factors HIF-1a, HIF-2a, and the prolyl hydroxylases in human prostate cancer (PMID:16278385)
• HIF-1alpha and HIF-2alpha mRNA levels are transiently increased in untrained human skeletal muscle in response to an acute exercise bout, but this response is blunted after exercise training. (PMID:16284786)
• In the normal, fully developed kidney, HIF-1alpha is expressed in most cell types, whereas HIF-2alpha is mainly found in renal interstitial fibroblast-like cells and endothelial cells (PMID:16554418)
• hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha stabilization and transactivation in a graded oxygen environment are regulated in a cell-specific manner (PMID:16760477)
• High HIF-2alpha expression is associated with head and neck cancer (PMID:16826581)
• HIF-P4H, HIF-1alpha and HIF-2alpha are effective oxygen sensors (PMID:16885164)
• knockdown of the HIF-2alpha gene demonstrated that HIF-2alpha regulates VEGF production, expression of which is essential in renal cell carcinoma (PMID:16920734)
• Results describe the differential recruitment of HIF-1alpha and HIF-2alpha to common target genes in neuroblastoma, and show that HIF-2alpha promotes an aggressive phenotype. (PMID:17097563)
• MT1-MMP is a major mediator of tumor cell invasiveness and type I collagen degradation by VHL RCC cells that express either MT1-MMP or HIF-2alpha (PMID:17140440)
• HIF2alpha C-terminal transactivation domain, in contrast to the HIF1alpha C-terminal transactivation domain, is relatively resistant to the inhibitory effects of FIH1 under normoxic conditions (PMID:17220275)
• Overexpression of the HIF-2A is associated with astrocytomas (PMID:17285230)
• discovery of a conserved, functional iron-responsive element (IRE) in the 5’ untranslated region of the messenger RNA encoding EPAS1 (PMID:17417656)
• The late expression of HIF-2alpha in the Barrett’s carcinogenesis sequence and its high expression in adenocarcinoma suggest it as a morker of disease progression. (PMID:17437013)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	epas1a	ENSDARG00000008697
danio_rerio	epas1b	ENSDARG00000057671
mus_musculus	Epas1	ENSMUSG00000024140
rattus_norvegicus	Epas1	ENSRNOG00000021318
drosophila_melanogaster	trh	FBGN0262139
drosophila_melanogaster	sima	FBGN0266411
caenorhabditis_elegans		WBGENE00001851

Paralogs (7): HIF1A (ENSG00000100644), SIM1 (ENSG00000112246), HIF3A (ENSG00000124440), NPAS1 (ENSG00000130751), NPAS3 (ENSG00000151322), SIM2 (ENSG00000159263), NPAS4 (ENSG00000174576)

Protein

Protein identifiers

Endothelial PAS domain-containing protein 1 — Q99814 (reviewed: Q99814)

Alternative names: Basic-helix-loop-helix-PAS protein MOP2, Class E basic helix-loop-helix protein 73, HIF-1-alpha-like factor, Hypoxia-inducible factor 2-alpha, Member of PAS protein 2, PAS domain-containing protein 2

All UniProt accessions (2): C9J9N2, Q99814

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5’-TACGTG-3’ within the hypoxia response element (HRE) of target gene promoters. Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX1 seems to activate CTAD.

Subunit / interactions. Interacts with HIF3A. Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5’-TACGTG-3’ within the hypoxia response element (HRE) of target gene promoters. Interacts with CREBBP. Interacts with EGLN1. Interacts with VHL. (Microbial infection) Interacts with Kaposi’s sarcoma-associated herpesvirus/HHV-8 protein ORF34; this interaction results in increased stability of EPAS1 and thus activation of its transcriptional activity.

Subcellular location. Nucleus. Nucleus speckle.

Tissue specificity. Expressed in most tissues, with highest levels in placenta, lung and heart. Selectively expressed in endothelial cells.

Post-translational modifications. In normoxia, is probably hydroxylated on Pro-405 and Pro-531 by EGLN1/PHD1, EGLN2/PHD2 and/or EGLN3/PHD3. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization. In normoxia, is hydroxylated on Asn-847 by HIF1AN thus probably abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. Phosphorylated on multiple sites in the CTAD. The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.

Disease relevance. Erythrocytosis, familial, 4 (ECYT4) [MIM:611783] An autosomal dominant disorder characterized by elevated serum hemoglobin and hematocrit, and normal platelet and leukocyte counts. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Several EPAS1 intronic variants have been identified, forming a unique haplotype in Tibetans, which has been proposed to allow them to thrive in a low-oxygen environment. The high-altitude adaptive haplotype is thought to have originated from Denisovans.

RefSeq proteins (1): NP_001421* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR001067	Nuc_translocat	Family
IPR001610	PAC	Repeat
IPR011598	bHLH_dom	Domain
IPR013767	PAS_fold	Domain
IPR014887	HIF-1_CTAD	Domain
IPR021537	HIF_alpha-like	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00989, PF08778, PF11413, PF14598, PF23171

UniProt features (51 total): sequence conflict 10, sequence variant 8, helix 7, strand 7, region of interest 6, domain 4, modified residue 4, turn 2, chain 1, compositionally biased region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

43 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3F1P	X-RAY DIFFRACTION	1.17
7Q5V	X-RAY DIFFRACTION	1.17
7Q5X	X-RAY DIFFRACTION	1.21
8Q64	X-RAY DIFFRACTION	1.36
8Q6E	X-RAY DIFFRACTION	1.37
8RV1	X-RAY DIFFRACTION	1.39
8Q6D	X-RAY DIFFRACTION	1.4
3F1N	X-RAY DIFFRACTION	1.48
8Q5S	X-RAY DIFFRACTION	1.49
3H82	X-RAY DIFFRACTION	1.5
4GHI	X-RAY DIFFRACTION	1.5
6D0C	X-RAY DIFFRACTION	1.5
6X21	X-RAY DIFFRACTION	1.54
9I64	X-RAY DIFFRACTION	1.56
3F1O	X-RAY DIFFRACTION	1.6
6CZW	X-RAY DIFFRACTION	1.6
6D0B	X-RAY DIFFRACTION	1.6
8RUT	X-RAY DIFFRACTION	1.62
3H7W	X-RAY DIFFRACTION	1.65
8RUV	X-RAY DIFFRACTION	1.66
4XT2	X-RAY DIFFRACTION	1.7
8CK3	X-RAY DIFFRACTION	1.71
4GS9	X-RAY DIFFRACTION	1.72
6I7Q	X-RAY DIFFRACTION	1.8
7UJV	X-RAY DIFFRACTION	1.8
8RUZ	X-RAY DIFFRACTION	1.82
5TBM	X-RAY DIFFRACTION	1.85
6D09	X-RAY DIFFRACTION	1.85
5UFP	X-RAY DIFFRACTION	1.9
6X28	X-RAY DIFFRACTION	1.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99814-F1	59.41	0.30

Functional residue map

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

Post-translational modifications (4): 405, 531, 840, 847

Mutagenesis-validated functional residues (1):

Position	Phenotype
844	abolishes hypoxia-inducible transcriptional activation of ctad.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1234158	Regulation of gene expression by Hypoxia-inducible Factor
R-HSA-1234174	Cellular response to hypoxia
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-452723	Transcriptional regulation of pluripotent stem cells
R-HSA-8849473	PTK6 Expression
R-HSA-8951664	Neddylation
R-HSA-9664873	Pexophagy
R-HSA-9909649	Regulation of PD-L1(CD274) transcription

MSigDB gene sets: 821 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, RNGTGGGC_UNKNOWN, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, MODULE_52, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, AAGCAAT_MIR137, MODULE_516, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_MYELOID_CELL_HOMEOSTASIS, HARRIS_HYPOXIA, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, JAEGER_METASTASIS_DN

GO Biological Process (28): angiogenesis (GO:0001525), response to hypoxia (GO:0001666), embryonic placenta development (GO:0001892), blood vessel remodeling (GO:0001974), regulation of heart rate (GO:0002027), epithelial cell maturation (GO:0002070), regulation of transcription by RNA polymerase II (GO:0006357), response to oxidative stress (GO:0006979), mitochondrion organization (GO:0007005), signal transduction (GO:0007165), visual perception (GO:0007601), erythrocyte differentiation (GO:0030218), lung development (GO:0030324), intracellular oxygen homeostasis (GO:0032364), norepinephrine metabolic process (GO:0042415), mRNA transcription by RNA polymerase II (GO:0042789), surfactant homeostasis (GO:0043129), positive regulation of transcription by RNA polymerase II (GO:0045944), myoblast fate commitment (GO:0048625), multicellular organismal-level iron ion homeostasis (GO:0060586), cellular response to hypoxia (GO:0071456), positive regulation of cold-induced thermogenesis (GO:0120162), regulation of protein neddylation (GO:2000434), regulation of DNA-templated transcription (GO:0006355), transcription by RNA polymerase II (GO:0006366), gene expression (GO:0010467), hemopoiesis (GO:0030097), cell differentiation (GO:0030154)

GO Molecular Function (13): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), protein dimerization activity (GO:0046983)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytosol (GO:0005829), nuclear speck (GO:0016607), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Cellular response to hypoxia	2
Cellular responses to stress	1
Developmental Biology	1
Signaling by PTK6	1
Post-translational protein modification	1
Selective autophagy	1
Regulation of PD-L1(CD274) expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transcription by RNA polymerase II	3
transcription cis-regulatory region binding	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
response to stress	2
regulation of DNA-templated transcription	2
multicellular organismal-level chemical homeostasis	2
regulation of transcription by RNA polymerase II	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
response to decreased oxygen levels	1
in utero embryonic development	1
placenta development	1
embryonic organ development	1
tissue remodeling	1
regulation of heart contraction	1
regulation of biological quality	1
epithelial cell development	1
cell maturation	1
organelle organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
sensory perception of light stimulus	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
respiratory tube development	1
animal organ development	1
respiratory system development	1
intracellular chemical homeostasis	1
catecholamine metabolic process	1
mRNA transcription	1
positive regulation of DNA-templated transcription	1
cell fate commitment	1
myoblast differentiation	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

4289 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPAS1	ARNT	P27540	991
EPAS1	RBM4	Q9BWF3	989
EPAS1	HIF1A	Q16665	984
EPAS1	HIF3A	Q9Y2N7	984
EPAS1	EGLN1	Q9GZT9	969
EPAS1	EGLN3	Q9H6Z9	967
EPAS1	VHL	P40337	967
EPAS1	EP300	Q09472	958
EPAS1	ARNT2	Q9HBZ2	953
EPAS1	EGLN2	Q96KS0	952
EPAS1	EIF5B	O60841	946
EPAS1	EIF4E2	O60573	940
EPAS1	MYC	P01106	929
EPAS1	POU5F1	P31359	906
EPAS1	SIRT7	Q9NRC8	893

IntAct

88 interactions, top by confidence:

A	B	Type	Score
VHL	ELOC	psi-mi:“MI:0914”(association)	0.920
EPAS1	ARNT	psi-mi:“MI:0407”(direct interaction)	0.890
EPAS1	ARNT	psi-mi:“MI:0915”(physical association)	0.890
ARNT	EPAS1	psi-mi:“MI:0915”(physical association)	0.890
ARNT	EPAS1	psi-mi:“MI:0407”(direct interaction)	0.890
EPAS1	VHL	psi-mi:“MI:0915”(physical association)	0.780
EPAS1	VHL	psi-mi:“MI:0914”(association)	0.780
EPAS1	EGLN1	psi-mi:“MI:0915”(physical association)	0.630
EGLN1	EPAS1	psi-mi:“MI:0915”(physical association)	0.630
EPAS1	EIF3E	psi-mi:“MI:0915”(physical association)	0.600
EIF3E	EPAS1	psi-mi:“MI:0915”(physical association)	0.600
EPAS1	EIF3E	psi-mi:“MI:0403”(colocalization)	0.600
FBP1	EPAS1	psi-mi:“MI:0915”(physical association)	0.600
FBP1	EPAS1	psi-mi:“MI:0407”(direct interaction)	0.600
EPAS1	RBM4	psi-mi:“MI:0915”(physical association)	0.580

BioGRID (275): EPAS1 (Biochemical Activity), Crebbp (Affinity Capture-Western), EP300 (Affinity Capture-Western), EPAS1 (Affinity Capture-Western), EPAS1 (Affinity Capture-Western), EPAS1 (Affinity Capture-Western), SMAD3 (Co-localization), VHL (Affinity Capture-Western), EGLN2 (Reconstituted Complex), EGLN1 (Reconstituted Complex), EGLN3 (Reconstituted Complex), EPAS1 (Affinity Capture-Western), HIF3A (Affinity Capture-Western), VHL (Affinity Capture-Western), EPAS1 (Affinity Capture-RNA)

ESM2 similar proteins: A0MLS5, G5EGD2, O00327, O02219, O02747, O02748, O15945, O35800, O44712, O88529, P27540, P30561, P35869, P41738, P41739, P53762, P56645, P79832, P97481, Q0PGG7, Q16665, Q17062, Q2VPD4, Q309Z6, Q5R4T2, Q61221, Q61324, Q6YGZ5, Q78E60, Q8K3T2, Q8QGQ7, Q8QGQ8, Q8R4S2, Q8R4S4, Q8R4S5, Q8R4S6, Q8R4S7, Q8WYA1, Q91YA9, Q95LD9

Diamond homologs: A1YFY6, A2T6X9, A9YTQ3, O09000, O35800, P05709, P81133, P97459, P97481, Q0PGG7, Q0VBL6, Q14190, Q16665, Q24119, Q24167, Q309Z6, Q61045, Q61079, Q61221, Q8IXF0, Q98SJ5, Q98SW2, Q99742, Q99814, Q9I8A9, Q9JHS1, Q9JHS2, Q9QZQ0, Q9XTA5, Q9Y2N7, Q9YIB9, A0MLS5, O00327, O02219, O02748, O15945, O61734, O88529, P27540, P41739

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
EPAS1	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	HBA1	“transcriptional regulation”
HIF3A	“down-regulates quantity by repression”	EPAS1	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	CACNA1A	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	PTPRZ1	“transcriptional regulation”
EPAS1	“down-regulates activity”	AP1	binding
EPAS1	“up-regulates quantity by expression”	KDM5B	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	KDM5C	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	KDM5A	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	KDM2A	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	KDM2B	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	KDM3A	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	KDM4B	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	KDM4C	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	KDM6B	“transcriptional regulation”
EPAS1	“up-regulates quantity by expression”	KDM7A	“transcriptional regulation”
EPAS1	“down-regulates quantity by repression”	KDM1A	“transcriptional regulation”
PIM1	“up-regulates quantity by stabilization”	EPAS1	phosphorylation
MAPK3	“up-regulates quantity by stabilization”	EPAS1	phosphorylation
MAPK1	“up-regulates quantity by stabilization”	EPAS1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 41 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	6	34.8×	7e-06
PPARA activates gene expression	5	13.9×	2e-03
Cellular responses to stress	6	6.5×	6e-03
Cellular responses to stimuli	6	5.5×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
response to hypoxia	7	19.1×	3e-05
cellular response to hypoxia	5	17.3×	5e-04
negative regulation of gene expression	6	11.8×	5e-04
protein stabilization	5	9.6×	4e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — PGNG.

Clinical variants and AI predictions

ClinVar

1825 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	4
Uncertain significance	988
Likely benign	649
Benign	90

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1699154	NM_001430.5(EPAS1):c.1604T>C (p.Met535Thr)	Pathogenic
6468	NM_001430.5(EPAS1):c.1609G>T (p.Gly537Trp)	Pathogenic
6469	NM_001430.5(EPAS1):c.1609G>A (p.Gly537Arg)	Pathogenic
6470	NM_001430.5(EPAS1):c.1603A>G (p.Met535Val)	Pathogenic
2920985	NM_001430.5(EPAS1):c.1601C>T (p.Pro534Leu)	Likely pathogenic
3777258	NM_001430.5(EPAS1):c.1573G>T (p.Asp525Tyr)	Likely pathogenic
3778704	NM_001430.5(EPAS1):c.1601C>G (p.Pro534Arg)	Likely pathogenic
4540647	NM_001430.5(EPAS1):c.1620C>G (p.Phe540Leu)	Likely pathogenic

SpliceAI

4041 predictions. Top by Δscore:

Variant	Effect	Δscore
17:55268084:CAGGT:C	donor_loss	1.0000
17:55268085:AGGT:A	donor_loss	1.0000
17:55268087:GTAA:G	donor_loss	1.0000
17:55315445:AAGG:A	donor_loss	1.0000
17:55315446:AG:A	donor_loss	1.0000
17:55315447:GG:G	donor_loss	1.0000
17:55315448:G:GA	donor_loss	1.0000
17:55315449:T:A	donor_loss	1.0000
17:55320648:T:A	acceptor_gain	1.0000
17:55320651:A:AG	acceptor_gain	1.0000
17:55320652:A:G	acceptor_gain	1.0000
17:55320655:A:AG	acceptor_gain	1.0000
17:55320799:G:GT	donor_gain	1.0000
17:55320816:G:GT	donor_gain	1.0000
17:55320817:A:T	donor_gain	1.0000
17:55320852:G:GG	donor_gain	1.0000
2:46346870:TA:T	acceptor_loss	1.0000
2:46346871:A:AC	acceptor_loss	1.0000
2:46346872:GGA:G	acceptor_gain	1.0000
2:46346872:GGAGT:G	acceptor_gain	1.0000
2:46347060:TCAGG:T	donor_loss	1.0000
2:46347061:CAGGT:C	donor_loss	1.0000
2:46347062:AGGTA:A	donor_loss	1.0000
2:46347063:GGTA:G	donor_loss	1.0000
2:46347064:GTAA:G	donor_loss	1.0000
2:46347065:T:A	donor_loss	1.0000
2:46356146:TCCA:T	acceptor_loss	1.0000
2:46356147:CCA:C	acceptor_loss	1.0000
2:46356149:A:AG	acceptor_gain	1.0000
2:46356149:A:G	acceptor_loss	1.0000

AlphaMissense

5797 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:46346905:G:C	R20P	1.000
2:46346956:T:C	L37P	1.000
2:46346968:T:C	L41P	1.000
2:46347000:G:C	D52H	1.000
2:46347001:A:C	D52A	1.000
2:46347001:A:T	D52V	1.000
2:46347003:A:C	K53Q	1.000
2:46347003:A:G	K53E	1.000
2:46347005:G:C	K53N	1.000
2:46347005:G:T	K53N	1.000
2:46347022:T:C	L59P	1.000
2:46356769:G:C	D139H	1.000
2:46360695:G:C	R171T	1.000
2:46360695:G:T	R171M	1.000
2:46360696:G:C	R171S	1.000
2:46360696:G:T	R171S	1.000
2:46360700:A:G	K173E	1.000
2:46360702:G:C	K173N	1.000
2:46360702:G:T	K173N	1.000
2:46360746:C:A	A188D	1.000
2:46360751:T:A	W190R	1.000
2:46360751:T:C	W190R	1.000
2:46360894:T:C	C195R	1.000
2:46361047:A:C	S246R	1.000
2:46361049:C:A	S246R	1.000
2:46361049:C:G	S246R	1.000
2:46380270:T:C	I533T	1.000
2:46346890:G:C	R15T	0.999
2:46346891:G:C	R15S	0.999
2:46346891:G:T	R15S	0.999

dbSNP variants (sampled 300 via entrez): RS1000016826 (2:46306610 A>G), RS1000045764 (2:46342905 T>C), RS1000058015 (2:46297535 C>T), RS1000067073 (2:46333820 A>G), RS1000093988 (2:46337377 C>T), RS1000131501 (2:46297706 C>T), RS1000145837 (2:46328852 G>A), RS1000247071 (2:46359289 T>A,C,G), RS1000299091 (2:46375239 C>T), RS1000358850 (2:46360250 C>T), RS1000362804 (2:46375905 G>A,C), RS1000397385 (2:46343151 C>G,T), RS1000416397 (2:46354075 A>G), RS1000478153 (2:46317140 C>G), RS1000479074 (2:46329855 CCTT>C)

Disease associations

OMIM: gene MIM:603349 | disease phenotypes: MIM:611783, MIM:613091, MIM:609820

GenCC curated gene-disease

Disease	Classification	Inheritance
erythrocytosis, familial, 4	Strong	Autosomal dominant
autosomal dominant secondary polycythemia	Supportive	Autosomal dominant

Mondo (5): erythrocytosis, familial, 4 (MONDO:0012729), teratoma (MONDO:0002601), asphyxiating thoracic dystrophy 3 (MONDO:0013127), erythrocytosis, familial, 3 (MONDO:0012353), (MONDO:0016599)

Orphanet (5): Autosomal dominant secondary polycythemia (Orphanet:247511), Jeune syndrome (Orphanet:474), Short rib-polydactyly syndrome, Majewski type (Orphanet:93269), Short rib-polydactyly syndrome, Saldino-Noonan type (Orphanet:93270), Short rib-polydactyly syndrome, Verma-Naumoff type (Orphanet:93271)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000405	Conductive hearing impairment
HP:0000740	Episodic paroxysmal anxiety
HP:0000790	Hematuria
HP:0000980	Pallor
HP:0000989	Pruritus
HP:0001069	Episodic hyperhidrosis
HP:0001095	Hypertensive retinopathy
HP:0001293	Cranial nerve compression
HP:0001337	Tremor
HP:0001342	Cerebral hemorrhage
HP:0001605	Vocal cord paralysis
HP:0001618	Dysphonia
HP:0001635	Congestive heart failure
HP:0001824	Weight loss
HP:0001899	Increased hematocrit
HP:0001900	Increased circulating hemoglobin concentration
HP:0001901	Polycythemia
HP:0001962	Palpitations
HP:0002018	Nausea
HP:0002331	Recurrent paroxysmal headache
HP:0002574	Episodic abdominal pain
HP:0002625	Deep venous thrombosis
HP:0002640	Hypertension associated with pheochromocytoma
HP:0002668	Paraganglioma
HP:0002864	Paraganglioma of head and neck
HP:0003072	Hypercalcemia
HP:0003345	Elevated urinary norepinephrine level

GWAS associations

36 associations (top):

Study	Trait	p-value
GCST000907_2	Renal cell carcinoma	2.000000e-09
GCST002835_1	Renal cell carcinoma	5.000000e-10
GCST002875_30	Diisocyanate-induced asthma	2.000000e-06
GCST003074_7	Cerebral amyloid deposition in APOEe4 non-carriers (PET imaging)	9.000000e-07
GCST004412_1	Craniofacial microsomia	1.000000e-17
GCST004652_2	Peak velocity of the mitral A-wave	3.000000e-07
GCST004826_14	P wave duration	1.000000e-09
GCST004826_3	P wave duration	1.000000e-10
GCST005146_3	Birth weight	2.000000e-29
GCST006054_5	High altitude adaptation	4.000000e-19
GCST006108_7	Facial morphology	3.000000e-07
GCST006108_8	Facial morphology	8.000000e-07
GCST006720_1	Hemoglobin levels	8.000000e-08
GCST006747_1	Oxygenated hemoglobin levels	6.000000e-09
GCST008226_3	Renal cell carcinoma	2.000000e-09
GCST008226_4	Renal cell carcinoma	1.000000e-06
GCST008226_5	Renal cell carcinoma	9.000000e-07
GCST008362_201	Birth weight	3.000000e-47
GCST008362_202	Birth weight	3.000000e-11
GCST008363_27	Offspring birth weight	1.000000e-18
GCST010002_390	Refractive error	1.000000e-11
GCST010320_143	PR interval	2.000000e-11
GCST010321_189	PR interval	2.000000e-12
GCST010796_1555	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_1556	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_1557	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-09
GCST010796_1558	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-09
GCST010796_1559	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_1560	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010796_1561	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0007707	cerebral amyloid deposition measurement
EFO:0008204	left ventricular diastolic function measurement
EFO:0005094	P wave duration
EFO:0004344	birth weight
EFO:0009105	high altitude adaptation
EFO:0004743	facial morphology
EFO:0004509	hemoglobin measurement
EFO:0005939	parental genotype effect measurement
EFO:0004462	PR interval
EFO:0004327	electrocardiography
EFO:0004980	appendicular lean mass
EFO:0004348	hematocrit

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D013724	Teratoma	C04.557.465.910
C565221	Erythrocytosis, Familial, 3 (supp.)
C567086	Erythrocytosis, Familial, 4 (supp.)
C537602	Short rib-polydactyly syndrome, Verma-Naumoff type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL1744522 (SINGLE PROTEIN), CHEMBL2221345 (PROTEIN FAMILY), CHEMBL3885518 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193763 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 520,006 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL4585668	BELZUTIFAN	4	1,088
CHEMBL50588	EMETINE	4	22,457
CHEMBL53463	DOXORUBICIN	4	314,282
CHEMBL84	TOPOTECAN	4	141,586
CHEMBL123292	CYCLOHEXIMIDE	2	39,732
CHEMBL383824	ALVESPIMYCIN	2	752
CHEMBL262344	BAKUCHIOL	1	109

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items; also 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
EPAS1 Overexpression	Belzutifan	Von Hippel-Lindau Disease	Sensitivity/Response	CIViC B	EID12948
EPAS1 Overexpression	Pazopanib	Renal Cell Carcinoma	Sensitivity/Response	CIViC B	EID1673

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1868089	Toxicity	3	sorafenib	Drug Toxicity
rs4035887	Toxicity	3	sorafenib	Drug Toxicity
rs7557402	Toxicity	3	sorafenib	Drug Toxicity
rs9973653	Toxicity	3	sorafenib	Drug Toxicity

PharmGKB variants

12 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1374749	EPAS1		0.00	0
rs3768728	EPAS1		0.00	0
rs4953344	EPAS1		0.00	0
rs6726454	EPAS1		0.00	0
rs7589621	EPAS1		0.00	0
rs9679290	EPAS1		0.00	0
rs12712973	EPAS1		0.00	0
rs1867785	EPAS1		0.00	0
rs1868089	EPAS1	3	3.00	1	sorafenib
rs7557402	EPAS1	3	3.00	1	sorafenib
rs4035887	EPAS1	3	1.50	1	sorafenib
rs9973653	EPAS1	3	3.00	1	sorafenib

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Hypoxia-inducible factors

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
belzutifan	Binding	8.05	pIC50
NVP-DFF332	Inhibition	8.05	pIC50
casdatifan	Binding	7.54	pIC50
PT2385	Binding	7.3	pKd

Binding affinities (BindingDB)

182 measured of 200 human assays (223 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL3335630	IC50	0.47 nM
CHEMBL3335423	IC50	0.97 nM
CHEMBL3335427	IC50	1.1 nM
CHEMBL3335426	IC50	2.6 nM
CHEMBL3335425	IC50	5.8 nM
(1S)-2,2-difluoro-4-[(7-fluoro-1H-indazol-4-yl)oxy]-7-(trifluoromethylsulfonyl)-1,3-dihydroinden-1-ol	IC50	19 nM	US-10597366: Aryl ethers and uses thereof
(1S)-2,2-difluoro-4-(1H-indazol-4-yloxy)-7-(trifluoromethylsulfonyl)-1,3-dihydroinden-1-ol	IC50	25 nM	US-10597366: Aryl ethers and uses thereof
3-[3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl]propanamide	IC50	47.9 nM
2,2-difluoro-4-[(7-fluoro-1H-indazol-4-yl)oxy]-7-(trifluoromethylsulfonyl)-1,3-dihydroinden-1-ol	IC50	68 nM	US-10597366: Aryl ethers and uses thereof
MLS000064750	IC50	113 nM
MLS000775145	EC50	201 nM
3-(2-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)sulfanylpropanoic acid	IC50	212 nM
2,2-difluoro-4-(1H-indazol-4-yloxy)-7-(trifluoromethylsulfonyl)-1,3-dihydroinden-1-ol	IC50	250 nM	US-10597366: Aryl ethers and uses thereof
3-(4-methyl-2-oxo-6,7,8,9-tetrahydrobenzofuro[3,2-g][1]benzopyran-3-yl)propanoic acid	IC50	276 nM
2-[4-[(4-tert-butylbenzoyl)amino]phenyl]acetic acid methyl ester	EC50	310 nM
SMR000208752	IC50	344 nM
3-[(4-methoxyphenoxy)methyl]benzoic acid	IC50	370 nM
(1S)-2,2-difluoro-4-[(5-fluoro-1H-indazol-4-yl)oxy]-7-(trifluoromethylsulfonyl)-1,3-dihydroinden-1-ol	IC50	380 nM	US-10597366: Aryl ethers and uses thereof
MLS000704718	IC50	391 nM
2-[4-[(3-methyl-2-furoyl)amino]phenyl]acetic acid	EC50	420 nM
4-[(E)-[[4-[(5-methyl-2-propan-2-ylphenoxy)methyl]benzoyl]hydrazinylidene]methyl]benzoic acid	IC50	450 nM
2-(2,4-dimethylphenyl)-5-benzotriazolamine	IC50	452 nM
cid_6351343	IC50	512 nM
3-[(2-chloranylphenoxy)methyl]benzoic acid	IC50	538 nM
4-[(6,7-difluoro-1H-indazol-4-yl)oxy]-2,2-difluoro-7-(trifluoromethylsulfonyl)-1,3-dihydroinden-1-ol	IC50	640 nM	US-10597366: Aryl ethers and uses thereof
4-[[4-(hydroximinomethyl)-2-methoxy-phenoxy]methyl]benzoic acid	IC50	670 nM
SMR000027953	IC50	832 nM
SMR001289802	IC50	858 nM
(3-aminophenyl)(3,4-dimethylphenyl)methanone	IC50	864 nM
butyl 4-[(4-bromo-2,5-dimethylpyrazole-3-carbonyl)carbamothioylamino]benzoate	IC50	894 nM
2-[4-(4-pyridin-2-ylpyrimidin-2-yl)phenoxy]ethanoic acid	IC50	913 nM
1-(3-nitrobenzyl)-1H-indole-3-carbaldehyde	IC50	978 nM
2,2-difluoro-4-[(5-fluoro-1H-indazol-4-yl)oxy]-7-(trifluoromethylsulfonyl)-1,3-dihydroinden-1-ol	IC50	1000 nM	US-10597366: Aryl ethers and uses thereof
N-[[4-[(4-bromophenyl)carbonylamino]phenyl]carbamothioyl]furan-2-carboxamide	IC50	1020 nM
cid_23605826	IC50	1040 nM
3-(5,7-dimethyl-2-phenyl-6-pyrazolo[1,5-a]pyrimidinyl)-1-(4-phenyl-1-piperazinyl)-1-propanone	IC50	1050 nM
MLS000715774	IC50	1050 nM
cid_2193280	IC50	1060 nM
methyl 2-[4-(4-pyridin-2-ylpyrimidin-2-yl)phenoxy]ethanoate	IC50	1070 nM
cid_18204049	IC50	1120 nM
3-[(N’‘E)-N’’-(2-thenylidene)hydrazino]benzoic acid	EC50	1310 nM
SMR000127789	IC50	1390 nM
MLS001140907	IC50	1410 nM
MLS000522533	IC50	1430 nM
(1,3-dioxoisoindol-2-yl) 4-ethylbenzenesulfonate	IC50	1550 nM
cid_1756351	IC50	1610 nM
cid_975543	IC50	1640 nM
2-[4-[(2-isopropyl-5-methyl-phenoxy)methyl]phenyl]-1,3,4-oxadiazole	EC50	1720 nM
5-Cyclopropyl-2H-pyrazole-3-carboxylic acid [1-thiophen-2-yl-eth-(Z)-ylidene]-hydrazide	EC50	1770 nM
3-(5,7-dimethyl-2-phenyl-6-pyrazolo[1,5-a]pyrimidinyl)-N-(2-furanylmethyl)propanamide	IC50	1810 nM

ChEMBL bioactivities

860 potent at pChembl≥5 of 968 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.62	Kd	0.24	nM	CHEMBL6133742
9.33	IC50	0.47	nM	CHEMBL3335630
9.01	IC50	0.97	nM	CHEMBL3335423
9.00	IC50	1	nM	CHEMBL5394054
9.00	IC50	1	nM	CHEMBL5427105
9.00	IC50	1	nM	CHEMBL5417823
8.96	IC50	1.1	nM	CHEMBL3335427
8.70	IC50	2	nM	CHEMBL4173075
8.70	EC50	2	nM	CHEMBL5590666
8.59	IC50	2.6	nM	CHEMBL3335426
8.52	IC50	3	nM	MANASSANTIN A
8.52	IC50	3	nM	MANASSANTIN B
8.52	IC50	3	nM	CHEMBL5414407
8.51	IC50	3.1	nM	CHEMBL3335421
8.51	Kd	3.1	nM	CHEMBL6145373
8.48	IC50	3.3	nM	CHEMBL3335415
8.44	IC50	3.6	nM	ALVESPIMYCIN
8.40	EC50	4	nM	CHEMBL4453227
8.40	IC50	4	nM	CHEMBL4639113
8.40	IC50	4	nM	CHEMBL4641092
8.30	IC50	5	nM	CHEMBL4172666
8.24	IC50	5.8	nM	CHEMBL3335425
8.22	EC50	6	nM	CHEMBL4165848
8.22	IC50	6	nM	CHEMBL5398227
8.22	IC50	6	nM	CHEMBL5440288
8.17	IC50	6.7	nM	CHEMBL6004325
8.15	IC50	7	nM	CHEMBL5397307
8.15	IC50	7	nM	CHEMBL5929123
8.10	IC50	7.9	nM	CHEMBL3335419
8.10	IC50	7.9	nM	CHEMBL3335411
8.10	IC50	8	nM	CHEMBL4165848
8.07	IC50	8.5	nM	CHEMBL4173075
8.06	IC50	8.7	nM	CRYPTOPLEURINE
8.05	EC50	9	nM	CHEMBL4162398
8.05	IC50	9	nM	BELZUTIFAN
8.05	IC50	9	nM	CHEMBL4453227
8.00	IC50	10	nM	CHEMBL4161350
8.00	EC50	10	nM	CHEMBL4175320
8.00	IC50	10	nM	BELZUTIFAN
7.96	IC50	11	nM	MANASSANTIN A
7.96	IC50	11	nM	CHEMBL4168513
7.96	EC50	11	nM	BELZUTIFAN
7.96	EC50	11	nM	CHEMBL5591431
7.96	IC50	11	nM	CHEMBL5764181
7.96	Kd	11	nM	CHEMBL6160361
7.92	IC50	12	nM	CHEMBL4173075
7.92	Kd	12	nM	CHEMBL6161996
7.92	IC50	12	nM	CHEMBL1098017
7.89	IC50	13	nM	CHEMBL3335416
7.89	IC50	13	nM	CHEMBL3335410

PubChem BioAssay actives

593 with measured affinity, of 1673 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
N-[4-[2-(1-adamantyl)ethynyl]phenyl]-4-[[(2S)-4-[[6-(2-methoxyethoxymethyl)-3-pyridinyl]methyl]-2-methylpiperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0005	uM
N-[4-[2-(1-adamantyl)ethynyl]phenyl]-4-[[4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0010	uM
3-[(4S)-5,5-difluoro-4-hydroxy-3-methylsulfonyl-4,6-dihydrocyclopenta[c]thiophen-1-yl]-5-fluorobenzonitrile	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0010	uM
(4S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methylsulfonyl-6,7-dihydro-4H-2-benzothiophen-4-ol	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0010	uM
3-chloro-5-[(4S)-5,5-difluoro-4-hydroxy-3-methylsulfonyl-6,7-dihydro-4H-2-benzothiophen-1-yl]benzonitrile	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0010	uM
N-[4-[2-(1-adamantyl)ethynyl]phenyl]-4-[[(2S)-4-[[6-(methoxymethyl)-3-pyridinyl]methyl]-2-methylpiperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0011	uM
3-fluoro-5-[[(4S,5S,6R)-2,2,3,3,5,6-hexafluoro-4-hydroxy-8-tricyclo[5.3.1.04,11]undeca-1(11),7,9-trienyl]oxy]benzonitrile	2117102: Inhibition of HIF-2alpha (unknown origin)	ec50	0.0020	uM
3-[[(1S)-2,2-difluoro-1-hydroxy-7-methylsulfonyl-1,3-dihydroinden-4-yl]oxy]-5-fluorobenzonitrile	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0020	uM
N-[4-[2-(1-adamantyl)ethynyl]phenyl]-4-[[(2S)-2-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0026	uM
(1R,2R)-1-(1,3-benzodioxol-5-yl)-2-[4-[(2S,3R,4R,5S)-5-[4-[(1R,2R)-1-(3,4-dimethoxyphenyl)-1-hydroxypropan-2-yl]oxy-3-methoxyphenyl]-3,4-dimethyloxolan-2-yl]-2-methoxyphenoxy]propan-1-ol	401552: Inhibition of hypoxia-induced HIF1 activation in human T47D cells after 16 hrs by pTK-HRE3-luciferase reporter gene assay	ic50	0.0030	uM
(4S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methylsulfonyl-4,6-dihydrocyclopenta[c]thiophen-4-ol	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0030	uM
2-[(1R,2R)-1-(3,4-dimethoxyphenyl)-1-hydroxypropan-2-yl]oxy-5-[(2S,3R,4R,5S)-5-[4-[(1R,2R)-1-(3,4-dimethoxyphenyl)-1-hydroxypropan-2-yl]oxy-3-methoxyphenyl]-3,4-dimethyloxolan-2-yl]phenol	726051: Inhibition of hypoxia-induced HIF1 transcriptional activity in human T47D cells by luciferase reporter gene assay	ic50	0.0030	uM
N-[4-(2-cyclohexylethynyl)phenyl]-4-[[4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0031	uM
4-[[(2S)-2-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0033	uM
[(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-[2-(dimethylamino)ethylamino]-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate	327961: Inhibition of hypoxia-induced HIF1 activation in human AGS cells by reporter gene assay	ic50	0.0036	uM
3-fluoro-5-[[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-1,3-dihydroinden-4-yl]oxy]benzonitrile	1516158: Inhibition of HIF-2alpha (unknown origin) expressed in human 786-O cells measured after 24 hrs by one-glo luciferase reporter gene assay	ec50	0.0040	uM
(4S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-methylsulfonyl-4,6-dihydrocyclopenta[c]thiophen-4-ol	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0040	uM
3-chloro-5-[(4S)-5,5-difluoro-4-hydroxy-3-methylsulfonyl-4,6-dihydrocyclopenta[c]thiophen-1-yl]benzonitrile	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0040	uM
4-(3-chloro-5-fluorophenoxy)-7-(difluoromethylsulfonyl)-2,3-dihydro-1H-inden-1-ol	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
3-[[(1S)-2,2-difluoro-7-(fluoromethylsulfonyl)-1-hydroxy-1,3-dihydroinden-4-yl]oxy]-5-fluorobenzonitrile	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
3-[[(1S)-2,2-difluoro-1-hydroxy-7-(trifluoromethylsulfonyl)-1,3-dihydroinden-4-yl]oxy]-5-fluorobenzonitrile	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
4-(3-chloro-5-fluorophenoxy)-7-(difluoromethylsulfonyl)-2,2-difluoro-1,3-dihydroinden-1-ol	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
5-(3-chloro-5-fluorophenoxy)-4-(difluoromethyl)-2,2-difluoro-1,1-dioxo-3H-1-benzothiophen-3-ol	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
4-bromo-5-(3-chloro-5-fluorophenoxy)-2,2-difluoro-1,1-dioxo-3H-1-benzothiophen-3-ol	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
5-(3-chloro-5-fluorophenoxy)-2,2-difluoro-1,1-dioxo-4-(trifluoromethyl)-3H-1-benzothiophen-3-ol	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
(1R)-4-(3-chloro-5-fluorophenoxy)-7-(difluoromethylsulfonyl)-2,3-dihydro-1H-inden-1-ol	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
N-(3-chloro-5-fluorophenyl)-2-nitro-4-(trifluoromethylsulfonyl)aniline	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
3-[[(1S)-7-(difluoromethylsulfonyl)-2,2-difluoro-1-hydroxy-1,3-dihydroinden-4-yl]oxy]-5-fluorobenzonitrile	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
3-[[(3R)-4-(difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxo-3H-1-benzothiophen-5-yl]oxy]-5-fluorobenzonitrile	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
N-[4-[2-(1-adamantyl)ethynyl]phenyl]-4-[[4-(2-aminopyridine-3-carbonyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0058	uM
(4S,5R)-1-(3-chloro-5-fluorophenyl)-5-fluoro-3-methylsulfonyl-5,6-dihydro-4H-cyclopenta[c]thiophen-4-ol	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0060	uM
3-[(4S)-5,5-difluoro-4-hydroxy-3-methylsulfonyl-6,7-dihydro-4H-2-benzothiophen-1-yl]-5-fluorobenzonitrile	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0060	uM
(4S)-1-(3,4-difluorophenyl)-5,5-difluoro-3-methylsulfonyl-6,7-dihydro-4H-2-benzothiophen-4-ol	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0070	uM
4-[[4-(pyridin-4-ylmethyl)piperazin-1-yl]methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0079	uM
N-[4-(2-phenylethynyl)phenyl]-4-[[4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0079	uM
(14aR)-2,3,6-trimethoxy-11,12,13,14,14a,15-hexahydro-9H-phenanthro[9,10-b]quinolizine	378016: Inhibition of hypoxia-induced HIF1 activation in human AGS cells after 16 hrs by pGL3-HRE-luciferase reporter gene assay	ic50	0.0087	uM
Belzutifan	1516157: Inhibition of N-(3-Chlorophenyl-4,6-t2)-4-nitrobenzo[c][1,2,5]oxadiazol-5-amine binding to his-tagged HIF-2alpha PAS-B domain (unknown origin) measured after 1 hr by scintillation proximity assay	ic50	0.0090	uM
3-[[7-(difluoromethylsulfonyl)-2,2-difluoro-1-hydroxy-1,3-dihydroinden-4-yl]oxy]-5-fluorobenzonitrile	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0100	uM
4-(difluoromethyl)-5-(3,5-difluorophenoxy)-2,2-difluoro-1,1-dioxo-3H-1-benzothiophen-3-ol	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0110	uM
(7R)-4-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol	2117102: Inhibition of HIF-2alpha (unknown origin)	ec50	0.0110	uM
2-methyl-4-[(11R)-2,8,11-trihydroxy-11-[(2R,5R)-5-[(2R,5R)-5-[(1R)-1-hydroxytridecyl]oxolan-2-yl]oxolan-2-yl]undecyl]-2H-furan-5-one	480174: Inhibition of hypoxia-induced HIF1 activation in human T47D cells in presence of 1% O2 by HRE3-TK-luc reporter assay	ic50	0.0120	uM
4-[(4-benzylpiperazin-1-yl)methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0130	uM
4-[[(2R)-2-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0130	uM
2-methyl-4-[(2R,8R,13R)-2,8,13-trihydroxy-13-[(2R,5R)-5-[(1R)-1-hydroxytridecyl]oxolan-2-yl]tridecyl]-2H-furan-5-one	480174: Inhibition of hypoxia-induced HIF1 activation in human T47D cells in presence of 1% O2 by HRE3-TK-luc reporter assay	ic50	0.0130	uM
3-[[4-(difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxo-3H-1-benzothiophen-5-yl]oxy]-5-fluorobenzonitrile	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0140	uM
4-[[4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0140	uM
N-(3-chloro-5-fluorophenyl)-4-(difluoromethylsulfonyl)-2-nitroaniline	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0160	uM
5-(3-chloro-5-fluorophenoxy)-2,2-difluoro-4-methyl-1,1-dioxo-3H-1-benzothiophen-3-ol	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0200	uM
4-chloro-5-(3-chloro-5-fluorophenoxy)-2,2-difluoro-1,1-dioxo-3H-1-benzothiophen-3-ol	1363249: Binding affinity to His-tagged HIF-2alpha PAS-B domain (unknown origin) after 2 hrs by scintillation proximity assay	ic50	0.0200	uM
(4S)-1-(3,4-difluorophenyl)-5,5-difluoro-3-methylsulfonyl-4,6-dihydrocyclopenta[c]thiophen-4-ol	1975371: Inhibition of human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged HIF-2alpha PAS-B domain (240 to 350 residues)/human recombinant N-terminal His6Gb1-TEV-GEFKGL-tagged and C-terminal FLAG-E362R-tagged ARNT PAS-B domain (356 to 470 residues) interaction preincubated for 15 mins at 23 degreeC and measured after 240 mins by Alphascreen analysis	ic50	0.0200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Oxygen	affects cotreatment, increases degradation, affects binding, decreases reaction, decreases expression (+4 more)	15
sodium arsenite	decreases hydroxylation, decreases ubiquitination, affects expression, decreases reaction, affects response to substance (+8 more)	10
cobaltous chloride	affects localization, decreases expression, increases response to substance, affects binding, affects reaction (+3 more)	7
Valproic Acid	affects cotreatment, increases expression	7
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression, affects expression	4
trichostatin A	affects cotreatment, increases expression	4
Deferoxamine	decreases reaction, increases degradation, increases expression, increases stability	4
Estradiol	decreases reaction, affects cotreatment, decreases expression	4
nickel sulfate	increases expression, affects cotreatment, affects reaction, decreases expression, increases degradation (+2 more)	3
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases hydroxylation, affects cotreatment, affects folding, decreases reaction, increases ubiquitination (+2 more)	3
Benzo(a)pyrene	affects cotreatment, decreases expression, increases abundance, affects response to substance	3
Hydrogen Peroxide	decreases reaction, increases expression, affects expression	3
Tretinoin	increases expression	3
Cyclosporine	decreases expression, increases expression	3
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases expression	3
aristolochic acid I	decreases expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression, affects cotreatment	2
Cycloheximide	decreases reaction, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Aflatoxin B1	increases methylation	2
Cadmium Chloride	decreases expression, affects folding, increases abundance, increases expression	2
4-(4-cyanophenyl)-2-(2-cyclopentylidenehydrazinyl)thiazole	decreases expression	1
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine	decreases reaction, increases expression	1
bisphenol F	decreases expression	1
TAK-243	increases sumoylation	1
VH298	affects cotreatment, affects folding, decreases expression, decreases reaction, increases expression (+1 more)	1
sotorasib	affects cotreatment, decreases expression	1

ChEMBL screening assays

241 unique, capped per target: 233 binding, 8 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1762876	Binding	Inhibition of HIF-2alpha activity in human 786-O cells by luciferase assay	Identification and evaluation of soft coral diterpenes as inhibitors of HIF-2α induced gene expression. — Bioorg Med Chem Lett
CHEMBL5723246	Functional	Affinity Biochemical interaction: (Scintillation proximity assay) EUB0002593a EPAS1	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 1 hybrid cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1F7	Abcam A-549 EPAS1 KO	Cancer cell line	Male
CVCL_F1MK	HyCyte AC16 KO-hEPAS1	Hybrid cell line
CVCL_F1MY	HyCyte BEAS-2B KO-hEPAS1	Transformed cell line	Male
CVCL_KT63	HeLa SilenciX Hif2alpha	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00104676	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Stage II or Stage III Germ Cell Tumors
NCT02375204	PHASE3	ACTIVE_NOT_RECRUITING	Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients with Relapsed or Refractory Germ Cell Tumors
NCT00002931	PHASE2	COMPLETED	Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Relapsed Germ Cell Cancer
NCT00301782	PHASE2	COMPLETED	Combination Chemotherapy in Treating Male Patients With Germ Cell Tumors
NCT00432094	PHASE2	COMPLETED	Autologous Peripheral Blood Stem Cell Transplant for Germ Cell Tumors
NCT00453232	PHASE2	COMPLETED	Combination Chemotherapy and Pegfilgrastim in Treating Men With Metastatic Germ Cell Tumors
NCT00453310	PHASE2	COMPLETED	Sunitinib in Treating Patients With Metastatic Germ Cell Tumors That Have Relapsed or Not Responded to Treatment
NCT00470366	PHASE2	COMPLETED	Combination Chemotherapy and Pegfilgrastim in Treating Patients With Previously Untreated Germ Cell Tumors
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NCT07199699	Not specified	NOT_YET_RECRUITING	Subxiphoid VATS for Giant Mediastinal Teratoma