EGLN3

Summary

EGLN3 (egl-9 family hypoxia inducible factor 3, HGNC:14661) is a protein-coding gene on chromosome 14q13.1, encoding Prolyl hydroxylase EGLN3 (Q9H6Z9). Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as PKM, TELO2, ATF4, GPX4 and HIF1A.

Enables peptidyl-proline 4-dioxygenase activity. Involved in protein hydroxylation. Located in cytosol and nucleus. Implicated in renal cell carcinoma. Biomarker of clear cell renal cell carcinoma.

Source: NCBI Gene 112399 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 20 total
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_022073

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14661
Approved symbol	EGLN3
Name	egl-9 family hypoxia inducible factor 3
Location	14q13.1
Locus type	gene with protein product
Status	Approved
Aliases	PHD3, HIFPH3
Ensembl gene	ENSG00000129521
Ensembl biotype	protein_coding
OMIM	606426
Entrez	112399

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding_CDS_not_defined, 5 protein_coding, 1 retained_intron

ENST00000250457, ENST00000464521, ENST00000487915, ENST00000546681, ENST00000547327, ENST00000548285, ENST00000550114, ENST00000551935, ENST00000553215, ENST00000556785, ENST00000557521, ENST00000929657

RefSeq mRNA: 2 — MANE Select: NM_022073 NM_001308103, NM_022073

CCDS: CCDS76671, CCDS9646

Canonical transcript exons

ENST00000250457 — 5 exons

Exon	Start	End
ENSE00001177397	33950396	33951074
ENSE00001295363	33924227	33925922
ENSE00001780608	33931096	33931215
ENSE00003508165	33926960	33927033
ENSE00003510746	33929076	33929212

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 97.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.0801 / max 342.6100, expressed in 931 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142770	6.2309	867
142769	0.2590	114
142772	0.1498	65
142773	0.1464	53
142777	0.1290	32
142768	0.1267	56
142776	0.0256	10
142775	0.0127	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	97.22	gold quality
skin of abdomen	UBERON:0001416	97.10	gold quality
apex of heart	UBERON:0002098	96.26	gold quality
heart left ventricle	UBERON:0002084	95.80	gold quality
right atrium auricular region	UBERON:0006631	95.73	gold quality
cardiac ventricle	UBERON:0002082	95.53	gold quality
zone of skin	UBERON:0000014	95.39	gold quality
lower esophagus mucosa	UBERON:0035834	95.15	gold quality
ventricular zone	UBERON:0003053	94.63	gold quality
cardiac atrium	UBERON:0002081	93.57	gold quality
heart	UBERON:0000948	93.02	gold quality
right uterine tube	UBERON:0001302	92.55	gold quality
rectum	UBERON:0001052	91.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.50	gold quality
amygdala	UBERON:0001876	90.41	gold quality
upper leg skin	UBERON:0004262	89.43	gold quality
body of stomach	UBERON:0001161	89.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.90	gold quality
right frontal lobe	UBERON:0002810	88.53	gold quality
spinal cord	UBERON:0002240	88.43	gold quality
nucleus accumbens	UBERON:0001882	88.41	gold quality
mucosa of transverse colon	UBERON:0004991	88.32	gold quality
colonic epithelium	UBERON:0000397	88.31	gold quality
lower esophagus	UBERON:0013473	88.30	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.25	gold quality
caudate nucleus	UBERON:0001873	88.14	gold quality
putamen	UBERON:0001874	88.12	gold quality
ileal mucosa	UBERON:0000331	87.96	gold quality
anterior cingulate cortex	UBERON:0009835	87.92	gold quality
stomach	UBERON:0000945	87.87	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	514.19
E-GEOD-100618	yes	185.51
E-MTAB-6678	yes	7.36
E-CURD-7	no	1033.79
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EPAS1, HIF1A, STAT1, STAT6, UNCX

miRNA regulators (miRDB)

150 targeting EGLN3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-570-3P	99.96	72.41	4910

Literature-anchored findings (GeneRIF, showing 40)

• siRNA targeted degradation of HIF-1alpha and HIF-2alpha results in decreased hypoxia-induced PHD3 expression (PMID:15156561)
• PHD1, PHD2, and PHD3 have roles in the regulation of hypoxia-inducible factor (PMID:15247232)
• results indicate that PHD3 is a TRiC substrate, providing another step at which PHD3 activity may be regulated (PMID:15251459)
• EglN3 acts downstream of c-Jun and is specifically required among the three EglN family members for neuronal apoptosis. (PMID:16098468)
• Mechanism underlying the regulation of PHD3 availability and activity in hypoxia by the E3 ligase Siah2. (PMID:16958618)
• The role of Siah2 phosphorylation in the regulation of its activity toward PHD3 is reported. (PMID:17003045)
• PHD-dependent oxygen-sensing recruits both the hypoxia-inducible factor (HIF) and ATF-4 systems. (PMID:17684156)
• The data demonstrates the cellular oxygen sensor PHD3 as a regulator of protein aggregation in response to varying oxygen availability. (PMID:18337469)
• Chronic hypoxia not only increases the pool of PHDs but also overactivates the three PHD isoforms. (PMID:18347341)
• Overexpression of the oxygen sensor PHD-3 is associated with tumor aggressiveness in pancreatic endocrine tumors. (PMID:18927305)
• Data show that PDK1 and HIF prolyl hydroxylase 3 mRNA expressions are lowest in children of chronic mountain sickness fathers at altitude. (PMID:18954447)
• Results describe the localization signal of HIF-prolyl hydroxylases (PHDs) 1-3, and their intracellular localization in response to hypoxia. (PMID:19339211)
• Interferon-gamma induces prolyl hydroxylase (PHD)3 through a STAT1-dependent mechanism in human endothelial cells. (PMID:19574556)
• interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. (PMID:19584355)
• BRCA1 tumours correlate with a HIF-1alpha phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression. (PMID:19724277)
• The CpG island of EGLN3 is frequently methylated in plasma cell dyscrasias and B-cell lymphomas. loss of EGLN3 is an important epigenetic event not only in plasma cell neoplasias but also in B-cell neoplasias. (PMID:19737309)
• PHD3 appears to be a tumor suppressor in colorectal cancer cells that inhibits IKKbeta/NF-kappaB signaling, independent of its hydroxylase activity. (PMID:19786027)
• our findings recognize the PHD/HIF regulatory axis as a novel therapeutic target to disable a tumor’s ability to adjust to hypoxic conditions and control cell survival (PMID:20028863)
• hPRP19 interacts with PHD3 to suppress the cell death under hypoxic conditions by limiting the function of PHD3 which leads to caspase activation (PMID:20599946)
• Methylation-induced epigenetic silencing of PHD1, PHD2, PHD3 and FIH is unlikely to underlie up-regulated HIF-1alpha expression in human breast cancer but may play a role in other tumour types. (PMID:20727020)
• Essential functions of PHD3 in pncreatic tumour growth, apoptosis and angiogenesis. (PMID:20978507)
• PHD3 expression is silenced by aberrant CpG methylation in a subset of human carcinoma cell lines of diverse origin and this aberrant cytosine methylation status is the mechanism by which these cancer cell lines fail to upregulate PHD3 mRNA (PMID:21297970)
• PHD3 has a role in regulating neutrophil survival in hypoxia (PMID:21317538)
• Prolyl hydroxylases (PHD3) regulate the transcriptional activity of HIF-1alpha. This could be potentially inhibited by polynitrogen compounds. (PMID:21421125)
• The oxygen sensor PHD3 limits glycolysis under hypoxia via direct binding to pyruvate kinase (PMID:21483450)
• these results suggest that PHD3 targets Pax2 for destruction. (PMID:21575608)
• Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1alpha and PKM2 coactivator function; PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells. (PMID:21620138)
• The expression of PHD genes and their relationship with the tumor behavior and apoptosis-associated factors in non-small cell lung cancer, was investigated. (PMID:21748337)
• PHD3 may be an important regulator of apoptosis and it is mainly found in tumors with good prognosis. (PMID:21877141)
• High tumor cell expression of PHD3 (P= 0.058) and FIH (P= 0.15) did not, however, reach statistical significance (PMID:21887331)
• a block in G1 to S transition in carcinoma cells under PHD3 inhibition (PMID:22087251)
• Overexpression of PHD3 is a favorable prognosticator for gastric cancer. (PMID:22290580)
• (R)-2HG, but not (S)-2HG, stimulates EGLN activity, leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes (PMID:22343896)
• Here, we outline specific functions of PHD enzymes in surgically relevant pathological conditions, and discuss how these functions might be exploited in order to support the treatment of surgically relevant diseases. (PMID:22395314)
• These results indicate that EGLN3 gene expression in macrophages is dependent on activin A (PMID:22778395)
• identification of HCLK2 as a substrate of PHD3 reveals the mechanism through which hypoxia inhibits the DDR, suggesting hydroxylation of HCLK2 is a potential therapeutic target for regulating the ATR/CHK1/p53 pathway (PMID:22797300)
• Our study has provided preliminary materials and data for further investigation of the effect of PHD3 on HepG2 cells (PMID:22898032)
• Egln3 suppresses glioma progression (PMID:22905089)
• Prolyl hydroxylase 3 (PHD3) modulates catabolic effects of tumor necrosis factor-alpha (TNF-alpha) on cells of the nucleus pulposus through co-activation of nuclear factor kappaB (NF-kappaB)/p65 signaling. (PMID:22948157)
• The data demonstrate p62 is a critical regulator of the hypoxia response and PHD3 activity, by inducing PHD3 aggregation and degradation under normoxia. (PMID:23345396)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	egln3	ENSDARG00000032553
mus_musculus	Egln3	ENSMUSG00000035105
rattus_norvegicus	Egln3	ENSRNOG00000005053

Paralogs (2): EGLN1 (ENSG00000135766), EGLN2 (ENSG00000269858)

Protein

Protein identifiers

Prolyl hydroxylase EGLN3 — Q9H6Z9 (reviewed: Q9H6Z9)

Alternative names: Egl nine homolog 3, HPH-1, Hypoxia-inducible factor prolyl hydroxylase 3, Prolyl hydroxylase domain-containing protein 3

All UniProt accessions (4): Q9H6Z9, F8VR39, F8W1G2, G3V3M1

UniProt curated annotations — full annotation on UniProt →

Function. Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as PKM, TELO2, ATF4, GPX4 and HIF1A. Target proteins are preferentially recognized via a LXXLAP motif. Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. Acts as an inhibitor of ferroptosis by mediating hydroxylation of GPX4, thereby preventing GPX4 degradation via chaperone-mediated autophagy. GPX4 hydroxylation is promoted by PSAT1, which provides 2-oxoglutarate substrate to EGLN3. ELGN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4.

Subunit / interactions. Interacts with BCL2 (via its BH4 domain); the interaction disrupts the BAX-BCL4 complex inhibiting the anti-apoptotic activity of BCL2. Interacts with WDR83; the interaction leads to almost complete elimination of HIF-mediated reporter activity. Interacts with ADRB2; the interaction hydroxylates ADRB2 facilitating its ubiquitination by the VHL-E3 ligase complex. Interacts with PAX2; the interaction targets PAX2 for destruction. Interacts with PKM; the interaction hydroxylates PKM in hypoxia. Interacts with LIMD1, WTIP and AJUBA.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Widely expressed at low levels. Expressed at higher levels in adult heart (cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle), lung and placenta, and in fetal spleen, heart and skeletal muscle. Also expressed in pancreas. Localized to pancreatic acini and islet cells.

Post-translational modifications. Ubiquitinated by SIAH1 and/or SIAH2 in response to the unfolded protein response (UPR), leading to its degradation.

Activity regulation. Activated in cardiovascular cells and Hela cells following exposure to hypoxia. Inhibited by polynitrogen compounds probably by chelation to Fe(2+) ions.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Domain organisation. The Beta(2)beta(3) ‘finger-like’ loop domain is important for substrate (HIFs’ CODD/NODD) selectivity.

Induction. Induced by hypoxia in a number of cells including neutrophils and certain cancer cell lines. Up-regulated 10-fold in pancreatic cancers.

RefSeq proteins (2): NP_001295032, NP_071356* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005123	Oxoglu/Fe-dep_dioxygenase_dom	Domain
IPR006620	Pro_4_hyd_alph	Domain
IPR044862	Pro_4_hyd_alph_FE2OG_OXY	Domain
IPR051559	HIF_prolyl_hydroxylases	Family

Pfam: PF13640

Enzyme classification (BRENDA):

• EC 1.14.11.2 — procollagen-proline 4-dioxygenase (BRENDA: 37 organisms, 182 substrates, 264 inhibitors, 251 Km, 44 kcat entries)
• EC 1.14.11.29 — hypoxia-inducible factor-proline dioxygenase (BRENDA: 7 organisms, 73 substrates, 125 inhibitors, 61 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

101 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.001–1	37
POLY(L-PROLINE)	0.0002–1.59	26
(L-PRO-L-PRO-GLY)10	0.015–2.9	15
(PRO-PRO-GLY)10	0.011–1.27	15
POLY(L-PRO)	0.002–0.65	15
FE2+	0.0004–0.016	9
O2	0.03–1.5	9
ASCORBATE	0.14–0.37	8
(L-PRO-L-PRO-GLY)5	0.12–1.8	6
PROTOCOLLAGEN	—	6
2-OXOGLUTARATE	0.0007–0.06	6
HYPOXIA-INDUCIBLE FACTOR-L-PROLINE	0.001–0.067	5
O2	0.1–0.76	5
(L-PRO-L-ALA-L-PRO-L-LYS)3	0.09–0.31	4
(SER-PRO)5	0.14–0.78	4

Catalyzed reactions (Rhea), 2 shown:

• L-prolyl-[hypoxia-inducible factor alpha subunit] + 2-oxoglutarate + O2 = trans-4-hydroxy-L-prolyl-[hypoxia-inducible factor alpha subunit] + succinate + CO2 (RHEA:48400)
• L-prolyl-[protein] + 2-oxoglutarate + O2 = trans-4-hydroxy-L-prolyl-[protein] + succinate + CO2 (RHEA:63484)

UniProt features (14 total): mutagenesis site 4, binding site 4, region of interest 2, sequence variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H6Z9-F1	91.44	0.82

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 (4): 135; 137; 196; 205

Mutagenesis-validated functional residues (4):

Position	Phenotype
91–102	abolishes interaction with adrb2 and no increase in cellular abundance of adrb2.
135	eliminates hydroxylase activity.
137	eliminates hydroxylase activity.
196	eliminates hydroxylase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha

MSigDB gene sets: 337 (showing top): GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOZGIT_ESR1_TARGETS_DN, DARWICHE_PAPILLOMA_PROGRESSION_RISK, RAMJAUN_APOPTOSIS_BY_TGFB1_VIA_SMAD4_DN, RAMJAUN_APOPTOSIS_BY_TGFB1_VIA_MAPK1_DN, NAGASHIMA_NRG1_SIGNALING_UP, CTCTAGA_MIR526C_MIR518F_MIR526A, MODULE_205, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_LEVELS, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, MARTINEZ_RB1_TARGETS_DN, KEGG_PATHWAYS_IN_CANCER, GOBP_RESPONSE_TO_OXYGEN_LEVELS, GOBP_PROTEIN_STABILIZATION

GO Biological Process (7): apoptotic process (GO:0006915), DNA damage response (GO:0006974), protein hydroxylation (GO:0018126), regulation of neuron apoptotic process (GO:0043523), protein stabilization (GO:0050821), cellular response to hypoxia (GO:0071456), negative regulation of ferroptosis (GO:0110076)

GO Molecular Function (11): ferrous iron binding (GO:0008198), 2-oxoglutarate-dependent dioxygenase activity (GO:0016706), L-ascorbic acid binding (GO:0031418), peptidyl-proline 4-dioxygenase activity (GO:0031545), hypoxia-inducible factor-proline dioxygenase activity (GO:0160082), iron ion binding (GO:0005506), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to hypoxia	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cellular response to stress	2
oxidoreductase activity	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
protein modification process	1
regulation of apoptotic process	1
neuron apoptotic process	1
regulation of protein stability	1
response to hypoxia	1
cellular response to decreased oxygen levels	1
negative regulation of programmed cell death	1
ferroptosis	1
regulation of ferroptosis	1
iron ion binding	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
dioxygenase activity	1
vitamin binding	1
carboxylic acid binding	1
monosaccharide binding	1
heterocyclic compound binding	1
peptidyl-proline dioxygenase activity	1
peptidyl-proline 4-dioxygenase activity	1
transition metal ion binding	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1294 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EGLN3	EPAS1	Q99814	967
EGLN3	HIF1A	Q16665	950
EGLN3	WDR83	Q9BRX9	945
EGLN3	SIAH2	O43255	938
EGLN3	ARNT	P27540	930
EGLN3	SIAH1	Q8IUQ4	873
EGLN3	VHL	P40337	870
EGLN3	ELOC	Q15369	782
EGLN3	ELOB	Q15370	779
EGLN3	HIF1AN	Q9NWT6	769
EGLN3	CUL2	Q13617	759
EGLN3	EPO	P01588	755
EGLN3	H3C1	P02295	752
EGLN3	H3-4	Q16695	752
EGLN3	H3-7	Q5TEC6	752
EGLN3	H3-5	Q6NXT2	752
EGLN3	H3C14	Q71DI3	752

IntAct

104 interactions, top by confidence:

A	B	Type	Score
EGLN3	HIF1A	psi-mi:“MI:0915”(physical association)	0.920
EGLN3	HIF1A	psi-mi:“MI:0210”(hydroxylation reaction)	0.920
HIF1A	EGLN3	psi-mi:“MI:0210”(hydroxylation reaction)	0.920
HIF1A	EGLN3	psi-mi:“MI:0915”(physical association)	0.920
FOXJ2	EGLN3	psi-mi:“MI:0915”(physical association)	0.720
EGLN3	FOXJ2	psi-mi:“MI:0915”(physical association)	0.720
MAPK6	EGLN3	psi-mi:“MI:0915”(physical association)	0.680
EGLN3	MAPK6	psi-mi:“MI:0915”(physical association)	0.680
REL	EGLN3	psi-mi:“MI:0915”(physical association)	0.670
VHL	HIF1A	psi-mi:“MI:0915”(physical association)	0.660
HIF1A	OS9	psi-mi:“MI:0914”(association)	0.650
EGLN3	HIF1A	psi-mi:“MI:0915”(physical association)	0.560
SERTAD1	EGLN3	psi-mi:“MI:0915”(physical association)	0.560
EGLN3	EFHC2	psi-mi:“MI:0915”(physical association)	0.560
EGLN3	NCAPH2	psi-mi:“MI:0915”(physical association)	0.560
EGLN3	TTC23L	psi-mi:“MI:0915”(physical association)	0.560
ABI2	EGLN3	psi-mi:“MI:0915”(physical association)	0.560
EFHC2	EGLN3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (1364): EGLN3 (Affinity Capture-Western), EGLN3 (Reconstituted Complex), EGLN3 (Two-hybrid), EGLN3 (Two-hybrid), EGLN3 (Two-hybrid), EGLN3 (Two-hybrid), EGLN3 (Two-hybrid), EGLN3 (Two-hybrid), EGLN3 (Two-hybrid), TTC23L (Two-hybrid), HIF1A (Co-localization), SQSTM1 (Co-localization), BIRC2 (Affinity Capture-Western), BIRC3 (Affinity Capture-Western), EGLN3 (Affinity Capture-Western)

ESM2 similar proteins: A1L251, A3KGZ2, A3KP85, A7SLX5, A8XFF4, B0X4N1, B8A4F4, O13648, O13730, O60066, O60157, O94450, O94632, P0CB42, P40032, P50244, Q01F03, Q09265, Q10313, Q11120, Q13686, Q19196, Q19910, Q19954, Q21407, Q22949, Q27883, Q28C22, Q3E9D5, Q3MI03, Q5R4R3, Q62630, Q6C3P4, Q6DE73, Q6GPQ5, Q75AW4, Q75B12, Q7JKC3, Q7K175, Q7YTB0

Diamond homologs: G5EBV0, P59722, Q62630, Q6AYU4, Q86KR9, Q91UZ4, Q91YE2, Q91YE3, Q96KS0, Q9GZT9, Q9H6Z9, C3RZA1, E1C5V0, Q0P585, Q7M6Z3, Q8R5A0, Q9NRG4

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
dimethyloxalylglycine	“down-regulates activity”	EGLN3	“chemical inhibition”
EGLN3	“down-regulates quantity by destabilization”	HIF1A	hydroxylation
Hypoxia	down-regulates	EGLN3
EGLN3	“up-regulates quantity by stabilization”	BCL2L11	hydroxylation
EGLN3	“down-regulates activity”	IKBKG	binding
EGLN3	“up-regulates quantity by stabilization”	ADRB2	hydroxylation
EGLN3	“up-regulates activity”	PKM	hydroxylation
EGLN3	“up-regulates activity”	PK	hydroxylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

923 predictions. Top by Δscore:

Variant	Effect	Δscore
14:33926958:A:AC	donor_gain	1.0000
14:33926959:C:CC	donor_gain	1.0000
14:33929070:TATTA:T	donor_loss	1.0000
14:33929071:ATTAC:A	donor_loss	1.0000
14:33929072:TTAC:T	donor_loss	1.0000
14:33929073:TACC:T	donor_loss	1.0000
14:33929074:A:T	donor_loss	1.0000
14:33929075:C:A	donor_loss	1.0000
14:33929208:TGTAG:T	acceptor_gain	1.0000
14:33929209:GTAG:G	acceptor_gain	1.0000
14:33929210:TAG:T	acceptor_gain	1.0000
14:33929210:TAGC:T	acceptor_loss	1.0000
14:33929211:AG:A	acceptor_gain	1.0000
14:33929211:AGC:A	acceptor_loss	1.0000
14:33929212:GCTGA:G	acceptor_loss	1.0000
14:33929213:C:CC	acceptor_gain	1.0000
14:33931091:AGTAC:A	donor_loss	1.0000
14:33931095:C:T	donor_loss	1.0000
14:33931212:TTGC:T	acceptor_gain	1.0000
14:33931213:TGC:T	acceptor_gain	1.0000
14:33931213:TGCC:T	acceptor_loss	1.0000
14:33931214:GC:G	acceptor_gain	1.0000
14:33931214:GCCTA:G	acceptor_loss	1.0000
14:33931215:CC:C	acceptor_gain	1.0000
14:33931216:C:CC	acceptor_gain	1.0000
14:33931216:CT:C	acceptor_loss	1.0000
14:33931217:T:G	acceptor_loss	1.0000
14:33944736:A:C	donor_gain	1.0000
14:33950390:TCCTA:T	donor_loss	1.0000
14:33950391:CCTA:C	donor_loss	1.0000

AlphaMissense

1555 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:33927017:A:G	W211R	1.000
14:33927017:A:T	W211R	1.000
14:33931163:T:A	D137V	1.000
14:33931163:T:G	D137A	1.000
14:33931164:C:G	D137H	1.000
14:33931168:G:C	H135Q	1.000
14:33931168:G:T	H135Q	1.000
14:33931170:G:C	H135D	1.000
14:33927015:C:A	W211C	0.999
14:33927015:C:G	W211C	0.999
14:33927033:T:A	R205S	0.999
14:33927033:T:G	R205S	0.999
14:33929076:C:G	R205T	0.999
14:33929102:G:C	H196Q	0.999
14:33929102:G:T	H196Q	0.999
14:33929104:G:C	H196D	0.999
14:33929142:T:A	D183V	0.999
14:33929151:G:T	P180H	0.999
14:33929152:G:A	P180S	0.999
14:33929193:C:G	R166P	0.999
14:33929203:C:A	G163W	0.999
14:33931105:C:A	W156C	0.999
14:33931105:C:G	W156C	0.999
14:33931107:A:G	W156R	0.999
14:33931107:A:T	W156R	0.999
14:33931133:G:A	T147I	0.999
14:33931143:G:T	R144S	0.999
14:33931145:C:A	G143V	0.999
14:33931145:C:T	G143D	0.999
14:33931159:G:C	N138K	0.999

dbSNP variants (sampled 300 via entrez): RS1000058478 (14:33940628 G>C), RS1000182950 (14:33936513 G>A), RS1000232779 (14:33931807 A>T), RS1000405346 (14:33949277 G>A,C,T), RS1000603036 (14:33941936 G>A,C), RS1000604198 (14:33944372 G>A), RS1000773460 (14:33937952 C>G), RS1000784219 (14:33935425 G>A,C), RS1000819593 (14:33925546 G>A), RS1000946399 (14:33937659 T>A), RS1001007660 (14:33951050 C>A,G,T), RS1001231174 (14:33950296 C>A,T), RS1001284832 (14:33943685 C>G,T), RS1001608225 (14:33943338 C>G), RS1001802631 (14:33949555 A>G)

Disease associations

OMIM: gene MIM:606426 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST003518_65	Daytime sleep phenotypes	4.000000e-06
GCST003518_94	Daytime sleep phenotypes	8.000000e-07
GCST004604_60	Hematocrit	3.000000e-09
GCST007511_18	Alzheimer’s disease (late onset)	3.000000e-06
GCST011369_36	Iron status biomarkers (ferritin levels)	3.000000e-41
GCST90002383_254	Hematocrit	3.000000e-21
GCST90002383_255	Hematocrit	2.000000e-13
GCST90002384_334	Hemoglobin	3.000000e-19
GCST90002384_335	Hemoglobin	3.000000e-11
GCST90002403_500	Red blood cell count	5.000000e-13
GCST90002403_501	Red blood cell count	9.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0004348	hematocrit
EFO:1001870	late-onset Alzheimers disease
EFO:0004459	ferritin measurement
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3831261 (PROTEIN FAMILY), CHEMBL5705 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 846,354 (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
CHEMBL3646221	VADADUSTAT	4	533
CHEMBL503160	FUMARIC ACID	3	845,433
CHEMBL3646118	MOLIDUSTAT	2	354
CHEMBL3931782	MOLIDUSTAT SODIUM	1	34

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1629140	EGLN3		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Prolyl hydroxylases

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

Ligand	Action	Affinity	Parameter
compound 6ee [PMID: 22364528]	Inhibition	8.46	pIC50
molidustat	Inhibition	6.31	pIC50

Binding affinities (BindingDB)

15 measured of 23 human assays (23 total across all organisms); most potent 15 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
PHD Inhibitor, 12{1,1,2}	IC50	35 nM
PHD Inhibitor, 12{2,3,2}	IC50	37.4 nM
PHD Inhibitor, 12{2,4,1}	IC50	38.3 nM
PHD Inhibitor, 12{4,1,2}	IC50	41.9 nM
PHD Inhibitor, 12{2,5,2}	IC50	44.8 nM
PHD Inhibitor, 12{2,6,2}	IC50	67.5 nM
PHD Inhibitor, 12{2,1,2}	IC50	93.8 nM
2-[[5-(4-cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid	IC50	99 nM	US-8598210: Prolyl hydroxylase inhibitors and methods of use
PHD Inhibitor, 12{2,3,4}	IC50	104 nM
PHD Inhibitor, 12{2,6,4}	IC50	113 nM
PHD Inhibitor, 12{2,1,4}	IC50	308 nM
PHD Inhibitor, 12{3,1,4}	IC50	1100 nM
PHD Inhibitor, 12{2,3,1}	IC50	1560 nM
PHD Inhibitor, 12{1,5,3}	IC50	2920 nM
2-[[5-(4-cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid	IC50	99000 nM	US-RE47437

ChEMBL bioactivities

176 potent at pChembl≥5 of 196 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.85	Kd	0.0142	nM	CHEMBL3133890
10.82	Kd	0.0152	nM	CHEMBL3133889
10.69	Kd	0.0202	nM	CHEMBL3133891
10.33	Kd	0.0469	nM	CHEMBL3133889
10.26	Kd	0.0544	nM	CHEMBL20724
10.11	Kd	0.0784	nM	CHEMBL3133888
10.08	Kd	0.0834	nM	CHEMBL3133892
9.10	IC50	0.8	nM	CHEMBL2041190
9.10	IC50	0.8	nM	CHEMBL3115284
9.10	IC50	0.8	nM	CHEMBL3115283
9.10	IC50	0.8	nM	CHEMBL3115282
9.00	IC50	1	nM	CHEMBL3115295
9.00	IC50	1	nM	CHEMBL3115296
9.00	IC50	1	nM	CHEMBL3115294
9.00	IC50	1	nM	CHEMBL3115293
9.00	IC50	1	nM	CHEMBL3115292
9.00	IC50	1	nM	CHEMBL3115291
9.00	IC50	1	nM	CHEMBL3115290
9.00	IC50	1	nM	CHEMBL3115289
9.00	EC50	1	nM	CHEMBL3115288
9.00	EC50	1	nM	CHEMBL3115287
9.00	IC50	1	nM	CHEMBL4173371
8.80	IC50	1.6	nM	CHEMBL2041175
8.80	IC50	1.6	nM	CHEMBL2041193
8.77	IC50	1.7	nM	CHEMBL2043169
8.72	IC50	1.9	nM	CHEMBL2043325
8.70	IC50	2	nM	CHEMBL2041010
8.70	IC50	2	nM	CHEMBL2041185
8.68	IC50	2.1	nM	CHEMBL2043168
8.68	IC50	2.1	nM	CHEMBL2041192
8.54	IC50	2.9	nM	CHEMBL2041188
8.49	IC50	3.2	nM	CHEMBL2041182
8.46	IC50	3.5	nM	CHEMBL2043010
8.46	IC50	3.5	nM	CHEMBL2041169
8.44	IC50	3.6	nM	CHEMBL2043324
8.39	IC50	4.1	nM	CHEMBL2041183
8.32	IC50	4.8	nM	CHEMBL2041189
8.31	IC50	4.9	nM	CHEMBL2041186
8.29	IC50	5.1	nM	CHEMBL4451025
8.26	IC50	5.5	nM	CHEMBL4163812
8.24	IC50	5.8	nM	CHEMBL2043326
8.24	IC50	5.8	nM	CHEMBL4561977
8.23	IC50	5.9	nM	CHEMBL2040897
8.22	IC50	6	nM	CHEMBL4476576
8.19	IC50	6.4	nM	CHEMBL2041164
8.19	IC50	6.4	nM	CHEMBL4462855
8.19	IC50	6.4	nM	CHEMBL4590677
8.18	IC50	6.6	nM	CHEMBL4452218
8.18	IC50	6.6	nM	CHEMBL4462741
8.18	IC50	6.6	nM	CHEMBL4474474

PubChem BioAssay actives

152 with measured affinity, of 224 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[[1-[(4-tert-butylphenyl)methyl]-2-(2,6-dichlorophenyl)-4-hydroxy-6-oxopyrimidine-5-carbonyl]amino]acetic acid	1067686: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli after 30 mins	ic50	0.0008	uM
3-methyl-4-[4-[8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-pyrazin-2-yl-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0008	uM
2-[[2-[(4-tert-butylphenyl)methyl]-6-(4-chlorophenyl)-5-hydroxy-3-oxopyridazine-4-carbonyl]amino]acetic acid	1067686: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli after 30 mins	ic50	0.0008	uM
2-[[1-benzyl-3-[(2-cyanophenyl)methyl]-6-hydroxy-2,4-dioxopyrimidine-5-carbonyl]amino]acetic acid	1067686: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli after 30 mins	ic50	0.0008	uM
2-[(6-hydroxy-7-pyridin-3-ylquinoxaline-5-carbonyl)amino]acetic acid	1067684: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli preincubated for 3 mins followed by substrate addition measured after 30 mins	ic50	0.0010	uM
2-[(7-hydroxy-3-phenylquinoline-8-carbonyl)amino]acetic acid	1067684: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli preincubated for 3 mins followed by substrate addition measured after 30 mins	ic50	0.0010	uM
2-[(1,7-dibenzylimidazo[4,5-f]benzimidazole-4-carbonyl)amino]acetic acid	1067684: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli preincubated for 3 mins followed by substrate addition measured after 30 mins	ic50	0.0010	uM
2-[(1-benzyl-6-bromo-5-hydroxybenzimidazole-4-carbonyl)amino]acetic acid	1067684: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli preincubated for 3 mins followed by substrate addition measured after 30 mins	ic50	0.0010	uM
N-[(4-chlorophenyl)methyl]-3-(5,6-dimethoxy-2-pyridinyl)-4-oxo-2-sulfanylidene-1H-thieno[3,2-d]pyrimidine-6-carboxamide	1067684: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli preincubated for 3 mins followed by substrate addition measured after 30 mins	ic50	0.0010	uM
N-[(4-chlorophenyl)methyl]-3-(5,6-dimethoxy-2-pyridinyl)-2,4-dioxo-1H-pyrido[4,3-d]pyrimidine-7-carboxamide	1067684: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli preincubated for 3 mins followed by substrate addition measured after 30 mins	ic50	0.0010	uM
N-(1,3-benzodioxol-5-ylmethyl)-3-(5,6-dimethoxy-2-pyridinyl)-2,4-dioxo-1H-thieno[3,2-d]pyrimidine-6-carboxamide	1067684: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli preincubated for 3 mins followed by substrate addition measured after 30 mins	ic50	0.0010	uM
N-[(4-chlorophenyl)methyl]-3-(5,6-dimethoxy-2-pyridinyl)-2,4-dioxo-1H-thieno[3,2-d]pyrimidine-6-carboxamide	1354505: Inhibition of His tagged MBP-PHD3 (1 to 230 residues) (unknown origin) expressed in Escherichia coli using Cy5-labelled HIF2alpha as substrate preincubated for 3 mins followed by substrate addition nmeasured after 30 mins by LANCE assay	ic50	0.0010	uM
2-[[1-benzyl-5-(benzylcarbamoyl)-4,6-dihydroxy-2-oxopyridine-3-carbonyl]amino]acetic acid	1067685: Inhibition of PHD3 in human Hep3B cells assessed as stimulation of EPO release after 48 hrs by ELISA	ec50	0.0010	uM
2-[[1-benzyl-5-(benzylcarbamoyl)-4-hydroxy-2-oxopyridine-3-carbonyl]amino]acetic acid	1067685: Inhibition of PHD3 in human Hep3B cells assessed as stimulation of EPO release after 48 hrs by ELISA	ec50	0.0010	uM
N-[(4-chlorophenyl)methyl]-3-(5,6-dimethoxy-2-pyridinyl)-5-methyl-4-oxo-2-sulfanylidene-1H-thieno[2,3-d]pyrimidine-6-carboxamide	1067684: Inhibition of 6His-tagged PHD3 (1 to 239) (unknown origin)-mediated Cy5CODD hydroxylation expressed in Escherichia coli preincubated for 3 mins followed by substrate addition measured after 30 mins	ic50	0.0010	uM
3-[4-(1,3-benzothiazol-5-yl)phenyl]-8-[(3-methyl-2-pyridinyl)methyl]-1-(6-oxo-1H-pyrimidin-4-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione	666422: Inhibition of PHD3	ic50	0.0016	uM
3-methyl-4-[4-[8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-pyrimidin-4-yl-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	1067672: Inhibition of PHD3 (unknown origin) expressed in Sf9 cells using HIF-1alpha peptide as substrate preincubated for 30 mins followed by substrate addition measured after 2 hrs by HTRF assay in presence of 2-oxoglutarate	ic50	0.0016	uM
3-[4-[1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0017	uM
4-[4-[1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]-3-methylbenzoic acid	666422: Inhibition of PHD3	ic50	0.0019	uM
5-[4-[1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]thiophene-2-carboxylic acid	666422: Inhibition of PHD3	ic50	0.0020	uM
4-[4-[1-(3-methoxypyrazin-2-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]-3-methylbenzoic acid	666422: Inhibition of PHD3	ic50	0.0020	uM
4-[4-[1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0021	uM
4-[4-[8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-pyrimidin-4-yl-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0021	uM
3-methyl-4-[4-[8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-pyrimidin-2-yl-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0029	uM
3-methyl-4-[4-[8-[(3-methyl-2-pyridinyl)methyl]-1-(6-methylpyrimidin-4-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0032	uM
8-[(3-methyl-2-pyridinyl)methyl]-1-(6-oxo-1H-pyrimidin-4-yl)-3-[4-[4-(1H-pyrazol-5-yl)phenyl]phenyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione	666422: Inhibition of PHD3	ic50	0.0035	uM
1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-3-(4-phenylphenyl)-1,3,8-triazaspiro[4.5]decane-6-carboxylic acid	666422: Inhibition of PHD3	ic50	0.0035	uM
3-fluoro-4-[4-[1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0036	uM
3-methyl-4-[4-[8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-[6-(trifluoromethyl)pyrimidin-4-yl]-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0041	uM
2-[[6-[[[(2S)-2-[[(2S)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-phenylpropanoyl]amino]methyl]-4-hydroxy-1-methyl-2-oxoquinoline-3-carbonyl]amino]acetic acid	1799910: PHD Enzymatic Assay from Article 10.1021/cc100073a: “Dipeptidyl-quinolone derivatives inhibit hypoxia inducible factor-1a prolyl hydroxylases-1, -2, and -3 with altered selectivity.”	ic50	0.0045	uM
4-[4-[8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-pyrazin-2-yl-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0048	uM
3-methyl-4-[4-[1-(3-methylpyrazin-2-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0049	uM
2-[[3-(4-cyanophenyl)-10-hydroxy-12-oxo-7-(trifluoromethoxy)-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5,7,9(13),10-tetraene-11-carbonyl]amino]acetic acid	1533130: Inhibition of recombinant human HIF-PHD3 expressed in baculovirus-infected Sf9 cells using biotin labelled DLDLEMLAPYIPMDDDFQL and 2-oxoglutarate as substrates preincubated for 30 mins followed by substrates addition and measured after 2 hrs by TR-FRET assay	ic50	0.0051	uM
2-[[6-[[[(2R)-2-[[(2R)-2-benzamido-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]methyl]-4-hydroxy-1-methyl-2-oxoquinoline-3-carbonyl]amino]acetic acid	1799910: PHD Enzymatic Assay from Article 10.1021/cc100073a: “Dipeptidyl-quinolone derivatives inhibit hypoxia inducible factor-1a prolyl hydroxylases-1, -2, and -3 with altered selectivity.”	ic50	0.0053	uM
2-[(1,3-dicyclohexyl-4-hydroxy-2,6-dioxopyrimidine-5-carbonyl)amino]acetic acid	1354494: Inhibition of PHD3 (unknown origin)	ic50	0.0055	uM
4-[4-[1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]-2-methylbenzoic acid	666422: Inhibition of PHD3	ic50	0.0058	uM
2-[[4-hydroxy-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl]amino]acetic acid	1533130: Inhibition of recombinant human HIF-PHD3 expressed in baculovirus-infected Sf9 cells using biotin labelled DLDLEMLAPYIPMDDDFQL and 2-oxoglutarate as substrates preincubated for 30 mins followed by substrates addition and measured after 2 hrs by TR-FRET assay	ic50	0.0058	uM
3-[4-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-8-[(3-methyl-2-pyridinyl)methyl]-1-(6-oxo-1H-pyrimidin-4-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione	666422: Inhibition of PHD3	ic50	0.0059	uM
2-[[4-hydroxy-2-oxo-1-[(1-phenylpyrazol-3-yl)methyl]-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl]amino]acetic acid	1533130: Inhibition of recombinant human HIF-PHD3 expressed in baculovirus-infected Sf9 cells using biotin labelled DLDLEMLAPYIPMDDDFQL and 2-oxoglutarate as substrates preincubated for 30 mins followed by substrates addition and measured after 2 hrs by TR-FRET assay	ic50	0.0060	uM
2-[[4-hydroxy-2-oxo-1-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl]amino]acetic acid	1533130: Inhibition of recombinant human HIF-PHD3 expressed in baculovirus-infected Sf9 cells using biotin labelled DLDLEMLAPYIPMDDDFQL and 2-oxoglutarate as substrates preincubated for 30 mins followed by substrates addition and measured after 2 hrs by TR-FRET assay	ic50	0.0064	uM
4-[4-[1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]thiophene-2-carboxylic acid	666422: Inhibition of PHD3	ic50	0.0064	uM
2-[[1-[(4-chlorophenyl)methyl]-4-hydroxy-2-oxo-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl]amino]acetic acid	1533130: Inhibition of recombinant human HIF-PHD3 expressed in baculovirus-infected Sf9 cells using biotin labelled DLDLEMLAPYIPMDDDFQL and 2-oxoglutarate as substrates preincubated for 30 mins followed by substrates addition and measured after 2 hrs by TR-FRET assay	ic50	0.0064	uM
2-[[6-[[[(2R)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-phenylpropanoyl]amino]methyl]-4-hydroxy-1-methyl-2-oxoquinoline-3-carbonyl]amino]acetic acid	1799910: PHD Enzymatic Assay from Article 10.1021/cc100073a: “Dipeptidyl-quinolone derivatives inhibit hypoxia inducible factor-1a prolyl hydroxylases-1, -2, and -3 with altered selectivity.”	ic50	0.0064	uM
2-[[1-(1,3-benzoxazol-2-ylmethyl)-4-hydroxy-2-oxo-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl]amino]acetic acid	1533130: Inhibition of recombinant human HIF-PHD3 expressed in baculovirus-infected Sf9 cells using biotin labelled DLDLEMLAPYIPMDDDFQL and 2-oxoglutarate as substrates preincubated for 30 mins followed by substrates addition and measured after 2 hrs by TR-FRET assay	ic50	0.0066	uM
2-[[4-hydroxy-2-oxo-1-[(2,4,5-trifluorophenyl)methyl]-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl]amino]acetic acid	1533130: Inhibition of recombinant human HIF-PHD3 expressed in baculovirus-infected Sf9 cells using biotin labelled DLDLEMLAPYIPMDDDFQL and 2-oxoglutarate as substrates preincubated for 30 mins followed by substrates addition and measured after 2 hrs by TR-FRET assay	ic50	0.0066	uM
2-[[10-hydroxy-12-oxo-3-[6-(trifluoromethyl)-3-pyridinyl]-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13),10-tetraene-11-carbonyl]amino]acetic acid	1533130: Inhibition of recombinant human HIF-PHD3 expressed in baculovirus-infected Sf9 cells using biotin labelled DLDLEMLAPYIPMDDDFQL and 2-oxoglutarate as substrates preincubated for 30 mins followed by substrates addition and measured after 2 hrs by TR-FRET assay	ic50	0.0066	uM
4-[4-[8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-(6-oxo-1H-pyrimidin-4-yl)-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0072	uM
3-methyl-4-[4-[8-[(3-methyl-2-pyridinyl)methyl]-1-(2-methylpyrimidin-4-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]phenyl]benzoic acid	666422: Inhibition of PHD3	ic50	0.0077	uM
2-[[4-hydroxy-2-oxo-1-[[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl]amino]acetic acid	1533130: Inhibition of recombinant human HIF-PHD3 expressed in baculovirus-infected Sf9 cells using biotin labelled DLDLEMLAPYIPMDDDFQL and 2-oxoglutarate as substrates preincubated for 30 mins followed by substrates addition and measured after 2 hrs by TR-FRET assay	ic50	0.0078	uM
2-[[4-hydroxy-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl]amino]acetic acid	1533130: Inhibition of recombinant human HIF-PHD3 expressed in baculovirus-infected Sf9 cells using biotin labelled DLDLEMLAPYIPMDDDFQL and 2-oxoglutarate as substrates preincubated for 30 mins followed by substrates addition and measured after 2 hrs by TR-FRET assay	ic50	0.0082	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment, decreases expression, affects expression, decreases methylation	9
Estradiol	increases expression, decreases expression, decreases reaction, affects cotreatment	5
methylmercuric chloride	decreases expression, increases expression, affects cotreatment	4
Oxygen	decreases reaction, increases expression	4
Particulate Matter	decreases expression, increases abundance, increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Cyclosporine	decreases expression	3
Aflatoxin B1	affects expression, increases expression	3
tungsten carbide	affects binding, increases expression, affects cotreatment	2
cobaltous chloride	increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	2
Ascorbic Acid	affects binding, affects cotreatment, increases expression	2
Cobalt	affects binding, increases expression, affects cotreatment	2
Copper	affects binding, affects expression, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression	2
Tobacco Smoke Pollution	decreases expression	2
Okadaic Acid	increases expression	2
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 expression, increases reaction	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, decreases expression	1
dimethylselenide	decreases expression, increases expression, increases oxidation	1
diethyl maleate	increases expression	1
nickel chloride	increases expression	1
potassium chromate(VI)	increases expression	1
ferrous chloride	decreases expression	1
andrographolide	increases expression	1

ChEMBL screening assays

54 unique, capped per target: 54 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4411721	Binding	Inhibition of PHD (unknown origin) expressed in mouse NIH/3T3 cells harboring HRE-driven luciferase gene assessed as transactivation of HIF1alpha after 6 hrs by luciferase reporter gene assay	Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors. — J Nat Prod

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8F4	Abcam HCT 116 EGLN3 KO	Cancer cell line	Male
CVCL_B9HC	Abcam A-549 EGLN3 KO	Cancer cell line	Male
CVCL_D2EX	Abcam MCF-7 EGLN3 KO	Cancer cell line	Female
CVCL_D9E3	Ubigene HEK293 EGLN3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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