EGLN2

Summary

EGLN2 (egl-9 family hypoxia inducible factor 2, HGNC:14660) is a protein-coding gene on chromosome 19q13.2, encoding Prolyl hydroxylase EGLN2 (Q96KS0). Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as ATF4, IKBKB, CEP192 and HIF1A.

The hypoxia inducible factor (HIF) is a transcriptional complex that is involved in oxygen homeostasis. At normal oxygen levels, the alpha subunit of HIF is targeted for degration by prolyl hydroxylation. This gene encodes an enzyme responsible for this post-translational modification. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream RAB4B (RAB4B, member RAS oncogene family) gene.

Source: NCBI Gene 112398 — RefSeq curated summary.

At a glance

• GWAS associations: 35
• Clinical variants (ClinVar): 627 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_080732

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14660
Approved symbol	EGLN2
Name	egl-9 family hypoxia inducible factor 2
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	PHD1, HIFPH1
Ensembl gene	ENSG00000269858
Ensembl biotype	protein_coding
OMIM	606424
Entrez	112398

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 23 protein_coding, 4 retained_intron

ENST00000303961, ENST00000406058, ENST00000593397, ENST00000593445, ENST00000593477, ENST00000593525, ENST00000593726, ENST00000593972, ENST00000594140, ENST00000594380, ENST00000595051, ENST00000595621, ENST00000596517, ENST00000597746, ENST00000598654, ENST00000599579, ENST00000601733, ENST00000602166, ENST00000863134, ENST00000863135, ENST00000863136, ENST00000863137, ENST00000936251, ENST00000936252, ENST00000962909, ENST00000962910, ENST00000962911

RefSeq mRNA: 2 — MANE Select: NM_080732 NM_053046, NM_080732

CCDS: CCDS12567

Canonical transcript exons

ENST00000303961 — 6 exons

Exon	Start	End
ENSE00001275650	40799191	40799262
ENSE00003557934	40807138	40807274
ENSE00003567073	40807484	40807551
ENSE00003598845	40806555	40806674
ENSE00003626383	40800339	40801415
ENSE00003851071	40807809	40808434

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 99.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.6578 / max 237.9970, expressed in 1819 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175905	28.7568	1819
175910	0.2836	121
175907	0.2651	97
175912	0.1952	61
175909	0.0597	13
175911	0.0528	12
175906	0.0348	9
175908	0.0099	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	99.22	gold quality
right testis	UBERON:0004534	99.19	gold quality
testis	UBERON:0000473	98.26	gold quality
blood	UBERON:0000178	97.96	gold quality
spleen	UBERON:0002106	97.90	gold quality
right lung	UBERON:0002167	97.08	gold quality
apex of heart	UBERON:0002098	97.05	gold quality
upper lobe of left lung	UBERON:0008952	96.85	gold quality
mucosa of transverse colon	UBERON:0004991	96.68	gold quality
primary visual cortex	UBERON:0002436	96.51	gold quality
putamen	UBERON:0001874	96.50	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.47	gold quality
granulocyte	CL:0000094	96.46	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.27	gold quality
myometrium	UBERON:0001296	96.26	gold quality
cerebellum	UBERON:0002037	96.26	gold quality
cerebellar hemisphere	UBERON:0002245	96.26	gold quality
cerebellar cortex	UBERON:0002129	96.25	gold quality
right lobe of thyroid gland	UBERON:0001119	96.24	gold quality
right frontal lobe	UBERON:0002810	96.24	gold quality
nucleus accumbens	UBERON:0001882	96.22	gold quality
Ammon’s horn	UBERON:0001954	96.19	gold quality
caudate nucleus	UBERON:0001873	96.16	gold quality
lymph node	UBERON:0000029	96.08	gold quality
right ovary	UBERON:0002118	96.06	gold quality
left lobe of thyroid gland	UBERON:0001120	96.04	gold quality
prefrontal cortex	UBERON:0000451	95.94	gold quality
endocervix	UBERON:0000458	95.92	gold quality
temporal lobe	UBERON:0001871	95.89	gold quality
amygdala	UBERON:0001876	95.88	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.59
E-MTAB-7606	no	543.87
E-GEOD-75367	no	363.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ARNT, ESR1

miRNA regulators (miRDB)

47 targeting EGLN2, 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-4673	100.00	66.64	1490
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
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-6845-3P	99.94	66.88	1439
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-1286	99.09	66.23	1046

Literature-anchored findings (GeneRIF, showing 40)

• identified a human homolog of Caenorhabditis elegans Egl9 as a HIF prolyl hydroxylase (PMID:12351678)
• effect of WT or mutated VHL on PHD 1, 2, and 3 (PMID:15156561)
• PHD1, PHD2, and PHD3 have roles in the regulation of hypoxia-inducible factor (PMID:15247232)
• defines the existence of two species of PHD1 and provide evidence that they are generated by alternative translational initiation (PMID:16509823)
• Understanding the mechanisms by which nickel can inhibit HIF-PHD’s and stabilize HIF-1alpha may be important in the treatment of cancer and ischemic diseases. (PMID:16649251)
• Multiple mitochondrial products, including tricarboxylic acid intermediates and reactive oxygen species, can coordinate PHD activity, HIF stabilization, and cellular responses to O(2) depletion. (PMID:17101781)
• hypoxia releases repression of NFkappaB activity through decreased prolyl hydroxylase-dependent hydroxylation of IKKbeta (PMID:17114296)
• Results describe the expression, purification and characterization of the human prolyl hydroxylase PHD1 in Escherichia coli. (PMID:18710826)
• The identification of EGLN2 as a significantly deregulated gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing network to the biology of renal oncocytoma. (PMID:18773095)
• Overexpression of the oxygen sensor PHD-1 is associated with tumor aggressiveness in pancreatic endocrine tumors. (PMID:18927305)
• The expression imbalance of HPH1 and FIH-1 in placenta may play an important role in the pathogenesis and development of severe pre-eclampsia through inhibiting HIF-1alpha. (PMID:19134330)
• Authors identify an interaction between melanoma antigen-11 (MAGE-11) cancer-testis antigen and the major HIF-alpha hydroxylating enzyme PHD2. (PMID:19147576)
• Prolyl hydroxylase inhibitor reduced mitochondrial cytochrome c release, nuclear translocation of apoptosis inducing factor (AIF), and promoted Akt phosphorylation (PMID:19229863)
• Results describe the localization signal of HIF-prolyl hydroxylases (PHDs) 1-3, and their intracellular localization in response to hypoxia. (PMID:19339211)
• these findings provide new insights into the mechanisms of the regulation of the oxygen sensor cascade of PHD1 and PHD2 in different cellular compartments. (PMID:19631610)
• Prolyl hydroxylase-dependent (but hypoxia inducible factor HIF-1alpha and -2alpha-independent) activation of hypoxia-induced monocyte-endothelial adhesion assigns a new function to monocytic ICAM-1 under acute hypoxic conditions. (PMID:20574001)
• role for PHD1 as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon (PMID:20600011)
• 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)
• human prolyl hydroxylase might play an important role in determining the physiology and structure of the corpora lutea during the menstrual cycle and early pregnancy (PMID:20840881)
• Elevated PHD1 concomitant with decreased PHD2 are causatively related to Rpb1 hydroxylation and oncogenesis in human renal clear cell carcinomas with WT VHL gene. (PMID:20978146)
• 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)
• PHD1 expression correlated with high proliferation, and these tumors were mainly estrogen receptor-negative. (PMID:21877141)
• PHD1 and PHD2 are independent negative prognostic factors in NSCLC. (PMID:21887331)
• Coexistence of PHD1 stabilized ATF4, as opposed to the destabilization of ATF4 by PHD3. (PMID:21951999)
• (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)
• miR-205 serves a protective role against both oxidative and endoplasmic reticulum stresses via the suppression of EGLN2 and subsequent decrease in intracellular reactive oxygen species. (PMID:22859986)
• Findings provided strong evidence for the hypothesis that rs10680577 contributes to hepatocarcinogenesis, possibly by affecting RERT-lncRNA structure and subsequently EGLN2 expression. (PMID:23026137)
• Principal component analysis of the covariance matrix of free AIRE-PHD1 highlights the presence of a “flapping” movement, which is blocked in an open conformation upon binding to H3K4me0. (PMID:23077531)
• Onconeuronal antigen Cdr2 correlates with HIF prolyl-4-hydroxylase PHD1 and worse prognosis in renal cell carcinoma. (PMID:23531419)
• By modulating Cep192 levels, PHD1 thereby affects the processes of centriole duplication and centrosome maturation and contributes to the regulation of cell-cycle progression. (PMID:23932902)
• Results show that variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk. (PMID:24045616)
• The diminished expression of PHD1 and PHD2 and elevated level of FIH protein in cancerous tissue compared to histopathologically unchanged colonic mucosa was not associated with DNA methylation within the CpG islands of the PHD1, PHD2 and FIH genes. (PMID:24195777)
• study conducted to investigate the association between gastric cancer (GC) susceptibility with a 4-bp insertion/deletion polymorphism (rs10680577) in the proximal promoter of EGLN2; findings showed that the heterozygote and the homozygote 4-bp del/del confer a significantly increased risk of GC (PMID:24517638)
• PHD-1 played an important role in hypoxic response pathway of trophoblast through modulating the level of HIF-2alpha. (PMID:24644426)
• Data indicate that the prolyl hydrolase 1 (PHD1) rs10680577 polymorphism is associated with the risk of non-small cell lung cancer in a Chinese population. (PMID:24894671)
• PHD1 could induce cell cycle arrest in lung cancer cells, resulting in the suppression of cell proliferation. (PMID:24935227)
• Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia (PMID:25263965)
• rs3733829 in the EGLN2 gene is significantly associated with the risk of COPD in Chinese populations of Hainan province. (PMID:25609945)
• EglN2 associates with the NRF1-PGC1alpha complex and controls mitochondrial function in breast cancer (PMID:26492917)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	egln2	ENSDARG00000062562
mus_musculus	Egln2	ENSMUSG00000058709
rattus_norvegicus	Egln2	ENSRNOG00000020947

Paralogs (2): EGLN3 (ENSG00000129521), EGLN1 (ENSG00000135766)

Protein

Protein identifiers

Prolyl hydroxylase EGLN2 — Q96KS0 (reviewed: Q96KS0)

Alternative names: Egl nine homolog 2, Estrogen-induced tag 6, HPH-3, Hypoxia-inducible factor prolyl hydroxylase 1, Prolyl hydroxylase domain-containing protein 1

All UniProt accessions (12): Q96KS0, A0A0C4DGR4, M0QXM8, M0QXR0, M0R035, M0R0Z6, M0R110, M0R1A3, M0R1L0, M0R1W4, M0R2X9, M0R350

UniProt curated annotations — full annotation on UniProt →

Function. Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as ATF4, IKBKB, CEP192 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. 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. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death. Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappa-B activation in hypoxic conditions. Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4.

Subunit / interactions. Interacts (preferably isoform p40) with SIAH2; the interaction targets both SIAH2 isoforms for proteasomal degradation in vitro. Interacts with LIMD1, WTIP and AJUBA.

Subcellular location. Nucleus.

Tissue specificity. Expressed in adult and fetal heart, brain, liver, lung, skeletal muscle, and kidney. Also expressed in testis and placenta. Highest levels in adult brain, placenta, lung, kidney, and testis. Expressed in hormone responsive tissues, including normal and cancerous mammary, ovarian and prostate epithelium.

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

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. By estrogen. Induced by proteasomal inhibitor MG132 (at protein level). Induced by hypoxia leading to protein stability. Repressed by hypoxia.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96KS0-1	p43, PHD1p43	yes
Q96KS0-2	p40, PHD1p40

RefSeq proteins (2): NP_444274, NP_542770* (*=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 (49 total): strand 13, mutagenesis site 12, helix 7, binding site 4, region of interest 4, compositionally biased region 2, chain 1, domain 1, modified residue 1, splice variant 1, sequence conflict 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5V1B	X-RAY DIFFRACTION	2.49

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96KS0-F1	69.05	0.48

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): 299; 358; 367; 297

Post-translational modifications (1): 130

Mutagenesis-validated functional residues (12):

Position	Phenotype
1	leads to expression of isoform p40 only.
34	leads to expression of isoform p43 only.
102	retained in the nucleus.
106	retained in the nucleus.
113	retained in the nucleus.
119	cytoplasmic and nuclear localization. reduced transcriptional activity of hif1a as for wild type.
134	retained in the nucleus.
297	eliminates hydroxylase activity.
299	eliminates hydroxylase activity.
358	eliminates hydroxylase activity.
367	eliminates hydroxylase activity.
367	eliminates hydroxylase activity on a hif1a peptide.

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: 222 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GGGTGGRR_PAX4_03, SP1_Q2_01, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_LEVELS, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (8): regulation of cell growth (GO:0001558), response to hypoxia (GO:0001666), peptidyl-proline hydroxylation to 4-hydroxy-L-proline (GO:0018401), estrogen receptor signaling pathway (GO:0030520), regulation of neuron apoptotic process (GO:0043523), cell redox homeostasis (GO:0045454), positive regulation of protein catabolic process (GO:0045732), cellular response to hypoxia (GO:0071456)

GO Molecular Function (12): ferrous iron binding (GO:0008198), 2-oxoglutarate-dependent dioxygenase activity (GO:0016706), oxygen sensor activity (GO:0019826), 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 (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

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
oxidoreductase activity	2
cellular anatomical structure	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
response to stress	1
response to decreased oxygen levels	1
modified amino acid metabolic process	1
peptidyl-proline hydroxylation	1
L-amino acid metabolic process	1
non-proteinogenic amino acid metabolic process	1
nuclear receptor-mediated steroid hormone signaling pathway	1
regulation of apoptotic process	1
neuron apoptotic process	1
cellular homeostasis	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
iron ion binding	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
dioxygenase activity	1
oxygen binding	1
molecular sensor 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

Protein interactions and networks

STRING

1248 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EGLN2	EPAS1	Q99814	952
EGLN2	HIF1A	Q16665	937
EGLN2	SIAH2	O43255	920
EGLN2	H3-3A	P06351	917
EGLN2	H3C14	Q71DI3	917
EGLN2	H3-5	Q6NXT2	917
EGLN2	H3C1	P02295	917
EGLN2	H3-4	Q16695	917
EGLN2	H3-7	Q5TEC6	917
EGLN2	SIAH1	Q8IUQ4	873
EGLN2	VHL	P40337	871
EGLN2	AIRE	O43918	867
EGLN2	ARNT	P27540	834
EGLN2	HIF1AN	Q9NWT6	768
EGLN2	EPO	P01588	762

IntAct

14 interactions, top by confidence:

A	B	Type	Score
EGLN2	HIF1A	psi-mi:“MI:0210”(hydroxylation reaction)	0.770
HIF1A	EGLN2	psi-mi:“MI:0915”(physical association)	0.770
VHL	HIF1A	psi-mi:“MI:0915”(physical association)	0.660
EGLN2	MFHAS1	psi-mi:“MI:0407”(direct interaction)	0.440
EGLN2	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
EPAS1	EGLN2	psi-mi:“MI:0915”(physical association)	0.400
PCNA	EGLN2	psi-mi:“MI:0915”(physical association)	0.370
TENT5A	EGLN2	psi-mi:“MI:0915”(physical association)	0.370
C1QTNF2	FCHO1	psi-mi:“MI:0914”(association)	0.350
ETS2	EGLN2	psi-mi:“MI:0915”(physical association)	0.000
MOB4	EGLN2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (53): DYRK1A (Affinity Capture-Western), DYRK1B (Affinity Capture-Western), EGLN2 (Reconstituted Complex), EGLN2 (Reconstituted Complex), CUL3 (Affinity Capture-Western), SPOP (Reconstituted Complex), EGLN2 (Reconstituted Complex), EGLN2 (Affinity Capture-Western), EGLN2 (Affinity Capture-RNA), EGLN2 (Reconstituted Complex), EGLN2 (Reconstituted Complex), ATF4 (Two-hybrid), ATF4 (Affinity Capture-Western), EGLN2 (Affinity Capture-Western), EGLN2 (Affinity Capture-Western)

ESM2 similar proteins: A0A2K3DDJ2, A2A9A2, A2VDX9, A2Y5N0, A4GRC6, A6QQ94, A8ICS9, A8ID95, A8INQ0, A8ITB0, A8ITV9, A8J666, A8JID5, F5A894, O83683, P09695, P09715, P14348, P17473, P24096, P28925, P30662, P54817, Q01JD1, Q08354, Q08355, Q08356, Q10MB4, Q2QPW2, Q49I55, Q49I57, Q4VKB4, Q5QD03, Q6AYU4, Q6F5E0, Q6L4N4, Q6S6U0, Q6SVX2, Q6SW04, Q7XT42

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

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
PRKCA	down-regulates	EGLN2	phosphorylation
dimethyloxalylglycine	“down-regulates activity”	EGLN2	“chemical inhibition”
SPOP	“down-regulates quantity by destabilization”	EGLN2	ubiquitination
FBXW7	“down-regulates quantity by destabilization”	EGLN2	ubiquitination
EGLN2	“down-regulates activity”	FOXO3	hydroxylation
EGLN2	“down-regulates quantity by destabilization”	HIF1A	hydroxylation
Hypoxia	down-regulates	EGLN2
EGLN2	“up-regulates activity”	ADSL	hydroxylation
MAPK9	“up-regulates activity”	EGLN2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	324
Likely benign	282
Benign	17

Top pathogenic / likely-pathogenic (0)

SpliceAI

1087 predictions. Top by Δscore:

Variant	Effect	Δscore
19:40799258:GCTCG:G	donor_gain	1.0000
19:40799268:G:GT	donor_gain	1.0000
19:40801414:AGG:A	donor_loss	1.0000
19:40801416:G:C	donor_loss	1.0000
19:40801416:G:T	donor_loss	1.0000
19:40807271:CCAGG:C	donor_loss	1.0000
19:40807272:CAG:C	donor_loss	1.0000
19:40807273:AG:A	donor_loss	1.0000
19:40807274:GG:G	donor_loss	1.0000
19:40807275:GTAT:G	donor_loss	1.0000
19:40807548:C:G	donor_gain	1.0000
19:40799259:C:G	donor_gain	0.9900
19:40799263:G:GG	donor_gain	0.9900
19:40799263:GT:G	donor_loss	0.9900
19:40799264:T:G	donor_loss	0.9900
19:40799287:G:GT	donor_gain	0.9900
19:40800337:A:AG	acceptor_gain	0.9900
19:40800338:G:GG	acceptor_gain	0.9900
19:40801414:AG:A	donor_gain	0.9900
19:40801415:GG:G	donor_gain	0.9900
19:40801416:G:GG	donor_gain	0.9900
19:40806666:G:T	donor_gain	0.9900
19:40806671:TAAGG:T	donor_loss	0.9900
19:40806673:AGG:A	donor_loss	0.9900
19:40806674:GGTA:G	donor_loss	0.9900
19:40806675:G:GC	donor_loss	0.9900
19:40807134:CCA:C	acceptor_loss	0.9900
19:40807135:CA:C	acceptor_loss	0.9900
19:40807135:CAG:C	acceptor_loss	0.9900
19:40807135:CAGGT:C	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000058022 (19:40800666 G>A,T), RS1000181343 (19:40804791 C>T), RS1000260619 (19:40801208 C>A,T), RS1000528182 (19:40805987 C>G,T), RS1000763607 (19:40804955 C>T), RS1000944865 (19:40805081 A>G), RS1001204310 (19:40798099 C>A), RS1001260374 (19:40802218 A>G), RS1001398949 (19:40801370 C>G,T), RS1001610245 (19:40808005 T>C), RS1002224899 (19:40806659 G>A,C), RS1002231423 (19:40797479 C>T), RS1002254499 (19:40806455 G>T), RS1002558940 (19:40808029 G>A), RS1002916880 (19:40798568 C>T)

Disease associations

OMIM: gene MIM:606424 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

35 associations (top):

Study	Trait	p-value
GCST000666_5	Smoking behavior	1.000000e-08
GCST001321_2	Chronic obstructive pulmonary disease	3.000000e-09
GCST003262_1080	Post bronchodilator FEV1	7.000000e-07
GCST003262_1083	Post bronchodilator FEV1	2.000000e-06
GCST003262_1091	Post bronchodilator FEV1	2.000000e-06
GCST003262_273	Post bronchodilator FEV1	4.000000e-06
GCST003262_274	Post bronchodilator FEV1	5.000000e-06
GCST003262_275	Post bronchodilator FEV1	4.000000e-06
GCST003262_538	Post bronchodilator FEV1	3.000000e-06
GCST003262_841	Post bronchodilator FEV1	4.000000e-06
GCST003264_1420	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_1479	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST004604_40	Hematocrit	6.000000e-11
GCST004615_122	Hemoglobin concentration	4.000000e-16
GCST004615_123	Hemoglobin concentration	1.000000e-09
GCST004976_2	Nicotine metabolite ratio in current smokers	6.000000e-26
GCST006701_2	Parental longevity (father’s attained age)	8.000000e-09
GCST007602_3	Smoking behaviour (cigarettes smoked per day)	2.000000e-09
GCST009921_7	Carotid intima media thickness (mean)	1.000000e-10
GCST010083_338	Hemoglobin levels	1.000000e-41
GCST90002383_282	Hematocrit	3.000000e-12
GCST90002383_283	Hematocrit	4.000000e-55
GCST90002383_284	Hematocrit	2.000000e-24
GCST90002383_285	Hematocrit	1.000000e-16
GCST90002384_452	Hemoglobin	4.000000e-14
GCST90002384_453	Hemoglobin	7.000000e-56
GCST90002384_465	Hemoglobin	5.000000e-25
GCST90002384_466	Hemoglobin	3.000000e-16
GCST90002403_297	Red blood cell count	4.000000e-09
GCST90002403_298	Red blood cell count	2.000000e-39

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004318	smoking behavior
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007794	nicotine metabolite ratio
EFO:0007796	parental longevity
EFO:0006525	cigarettes per day measurement
EFO:0004305	erythrocyte count
EFO:0004533	alkaline phosphatase measurement
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3028 (SINGLE PROTEIN), CHEMBL3831261 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 388 (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
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
rs3733829	EGLN2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Prolyl hydroxylases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 6ee [PMID: 22364528]	Inhibition	9.7	pIC50

Binding affinities (BindingDB)

473 measured of 476 human assays (476 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-{5- [(cyclopropylmethyl) amino]-[1,2,4] triazolo [1,5-a]pyrimidin-7- yl}benzonitrile	IC50	5 nM	US-10287286: Compounds
4-{7-[(oxetan-3- ylmethyl)amino]- [1,2,4]triazolo[1,5- a]pyridin-5- yl}benzonitrile	IC50	5 nM	US-10287286: Compounds
4-(7-{[(4- fluorophenyl) methyl]amino}- [1,2,4]triazolo[1,5- a]pyridin-5- yl)benzonitrile	IC50	5 nM	US-10287286: Compounds
4-(7-{[2- (dimethylamino) ethyl]amino}- [1,2,4]triazolo[1,5- a]pyridin-5- yl)benzonitrile	IC50	8 nM	US-10287286: Compounds
4-{7- [(cyclopropyl- methyl) amino]- [1,2,4]triazolo[1,5- a]pyridin-5- yl}benzonitrile	IC50	9 nM	US-10287286: Compounds
4-{7-[(3,3,3- trifluoropropyl) amino]- [1,2,4]triazolo[1,5- a]pyridin-5- yl}benzonitrile	IC50	9 nM	US-10287286: Compounds
4-{7-[(2,2- difluoroethyl) amino]- [1,2,4]triazolo[1,5- a]pyridin-5- yl}benzonitrile	IC50	10 nM	US-10287286: Compounds
2-fluoro-4-([1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile	IC50	10 nM	US-10287286: Compounds
4-[5- (dimethylamino)- [1,2,4]triazolo[1,5- a]pyrimidin-7- yl]benzonitrile	IC50	11 nM	US-10287286: Compounds
1-[5-(4-cyano-3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-3-phenylurea	IC50	12 nM	US-10287286: Compounds
4-(7-{[(2- fluorophenyl) methyl]amino}- [1,2,4]triazolo[1,5- a]pyridin-5- yl)benzonitrile	IC50	13 nM	US-10287286: Compounds
4-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile	IC50	13 nM	US-10287286: Compounds
cyclopropylmethyl N-[5-(4- cyano-3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 7-yl]carbamate	IC50	14 nM	US-10287286: Compounds
6-methyl-5-(7-oxo-3H-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridine-2-carbonitrile	IC50	17 nM	US-10287286: Compounds
4-{7-[(oxolan-2- ylmethyl)amino]- [1,2,4]triazolo[1,5- a]pyridin-5- yl}benzonitrile	IC50	20 nM	US-10287286: Compounds
4-{7-[(oxolan-3- ylmethyl)amino]- [1,2,4]triazolo[1,5- a]pyridin-5- yl}benzonitrile	IC50	25 nM	US-10287286: Compounds
4,6-dimethyl-5-([1,2,4]triazolo[1,5-a]pyridin-5-yl)pyrimidine-2-carbonitrile	IC50	25 nM	US-10287286: Compounds
4-[7-(ethylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]benzonitrile	IC50	25 nM	US-10287286: Compounds
4-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-fluorobenzonitrile	IC50	27 nM	US-10287286: Compounds
3-methyl-4-(7-oxo-3H-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile	IC50	27 nM	US-10287286: Compounds
N-[5-(4-cyano-3- fluorophenyl)- [1,2,4]triazolo[1,5- a]pyridin-7-yl]- 3,3,3- trifluoro- propanamide	IC50	28 nM	US-10287286: Compounds
4-(5-{[3- (dimethylamino) propyl]amino}- [1,2,4]triazolo[1,5- a]pyrimidin-7- yl)benzonitrile	IC50	29 nM	US-10287286: Compounds
4-(7-{[(3- fluorophenyl) methyl]amino}- [1,2,4]triazolo[1,5- a]pyridin-5- yl)benzonitrile	IC50	29 nM	US-10287286: Compounds
4-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2,3-difluorobenzonitrile	IC50	29 nM	US-10287286: Compounds
2-fluoro-4-(7-oxo-3H-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile	IC50	30 nM	US-10287286: Compounds
4-[5- (cyclopropylamino)- [1,2,4]triazolo[1,5- a]pyrimidin-7- yl]benzonitrile	IC50	32 nM	US-10287286: Compounds
4-[7-(benzylamino)- [1,2,4]triazolo[1,5- a]pyridin-5- yl]benzonitrile	IC50	33 nM	US-10287286: Compounds
4-{7-(2- methoxyethyl) amino}- [1,2,4]triazolo[1,5- a]pyridin-5- yl}benzonitrile	IC50	34 nM	US-10287286: Compounds
N-[5-(4-cyano-3- fluorophenyl)- [1,2,4]triazolo[1,5- a]pyridin-7-yl] cyclopropane- carboxamide	IC50	34 nM	US-10287286: Compounds
2,6-difluoro-4-([1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile	IC50	34 nM	US-10287286: Compounds
4-([1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile	IC50	34 nM	US-10287286: Compounds
5-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-4-methylpyridine-2-carbonitrile	IC50	35 nM	US-10287286: Compounds
PHD Inhibitor, 12{1,1,2}	IC50	35 nM
4-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3-fluorobenzonitrile	IC50	36 nM	US-10287286: Compounds
4-{7-[(oxan-4- ylmethyl)amino]- [1,2,4]triazolo[1,5- a]pyridin-5- yl}benzonitrile	IC50	37 nM	US-10287286: Compounds
PHD Inhibitor, 12{2,3,2}	IC50	37.4 nM
PHD Inhibitor, 12{2,4,1}	IC50	38.3 nM
4-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile	IC50	39 nM	US-10287286: Compounds
4-(7-benzylsulfanyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile	IC50	40 nM	US-10287286: Compounds
PHD Inhibitor, 12{4,1,2}	IC50	41.9 nM
N-[5-(4- cyanophenyl)- [1,2,4]triazolo[1,5- a]pyridin-7-yl]-2- phenylacetamide	IC50	42 nM	US-10287286: Compounds
PHD Inhibitor, 12{2,5,2}	IC50	44.8 nM
2-fluoro-4-(7-{[(3- methyloxetan-3- yl)methyl]amino}- [1,2,4]triazolo[1,5- a]pyridin-5- yl)benzonitrile	IC50	47 nM	US-10287286: Compounds
N-[5-(4- cyanophenyl)- [1,2,4]triazolo[1,5- a]pyridin-7-yl]-3- methoxy- propanamide	IC50	47 nM	US-10287286: Compounds
4-[7-(benzyloxy)- [1,2,4]triazolo[1,5- a]pyridin-5- yl]benzonitrile	IC50	49 nM	US-10287286: Compounds
tert-butyl N-[5-(4- cyano-3- fluorophenyl)- [1,2,4]triazolo[1,5- a]pyridin-7- yl]carbamate	IC50	49 nM	US-10287286: Compounds
N-[5-(4-cyano-3- fluorophenyl)- [1,2,4]triazolo[1,5- a]pyridin-5-yl]-2- cyclopropyl- acetamide	IC50	49 nM	US-10287286: Compounds
tert-butyl 6-[3-oxo-4-(triazol-1-yl)-1H-pyrazol-2-yl]pyridine-3-carboxylate	IC50	50 nM	US-8653111: Substituted dihydropyrazolones for treating cardiovascular and hematological diseases
3-fluoro-4-([1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile	IC50	50 nM	US-10287286: Compounds
tert-butyl N-[5-(4- cyanophenyl)- [1,2,4]triazolo[1,5- a]pyridin-7- yl]carbamate	IC50	52 nM	US-10287286: Compounds

ChEMBL bioactivities

584 potent at pChembl≥5 of 632 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	IC50	0.2	nM	CHEMBL2043169
9.70	IC50	0.2	nM	CHEMBL2043325
9.70	IC50	0.2	nM	CHEMBL2041169
9.70	IC50	0.2	nM	CHEMBL2041175
9.70	IC50	0.2	nM	CHEMBL2041182
9.70	IC50	0.2	nM	CHEMBL2041185
9.70	IC50	0.2	nM	CHEMBL2041190
9.70	IC50	0.2	nM	CHEMBL2041193
9.52	IC50	0.3	nM	CHEMBL2043168
9.52	IC50	0.3	nM	CHEMBL2043326
9.52	IC50	0.3	nM	CHEMBL2041010
9.52	IC50	0.3	nM	CHEMBL2041178
9.52	IC50	0.3	nM	CHEMBL2041184
9.52	IC50	0.3	nM	CHEMBL2041186
9.52	IC50	0.3	nM	CHEMBL2041188
9.52	IC50	0.3	nM	CHEMBL2041192
9.40	IC50	0.4	nM	CHEMBL2043324
9.40	IC50	0.4	nM	CHEMBL2040897
9.40	IC50	0.4	nM	CHEMBL2041183
9.40	IC50	0.4	nM	CHEMBL2041189
9.30	IC50	0.5	nM	CHEMBL2041170
9.30	IC50	0.5	nM	CHEMBL2040854
9.15	IC50	0.7	nM	CHEMBL2041177
9.10	IC50	0.8	nM	CHEMBL2041164
9.10	IC50	0.8	nM	CHEMBL2041171
9.05	IC50	0.9	nM	CHEMBL2043171
9.00	IC50	1	nM	CHEMBL2041191
9.00	IC50	1	nM	CHEMBL2041194
9.00	IC50	1	nM	CHEMBL4783524
8.96	IC50	1.1	nM	CHEMBL2043010
8.96	IC50	1.1	nM	CHEMBL2043011
8.96	IC50	1.1	nM	CHEMBL2041176
8.96	IC50	1.1	nM	CHEMBL2041180
8.92	IC50	1.2	nM	CHEMBL2043172
8.92	IC50	1.2	nM	CHEMBL2041187
8.89	IC50	1.3	nM	CHEMBL2043004
8.85	IC50	1.4	nM	CHEMBL2043003
8.85	IC50	1.4	nM	CHEMBL2043006
8.85	IC50	1.4	nM	CHEMBL2043007
8.85	IC50	1.4	nM	CHEMBL4451025
8.80	IC50	1.6	nM	CHEMBL2041181
8.77	IC50	1.7	nM	CHEMBL2043005
8.74	IC50	1.8	nM	CHEMBL2043002
8.74	IC50	1.8	nM	CHEMBL2041174
8.72	IC50	1.9	nM	CHEMBL2043327
8.70	IC50	2	nM	CHEMBL2041167
8.68	IC50	2.1	nM	CHEMBL2043008
8.68	IC50	2.1	nM	CHEMBL2041172
8.68	IC50	2.1	nM	CHEMBL4462855
8.68	IC50	2.1	nM	CHEMBL4443606

PubChem BioAssay actives

171 with measured affinity, of 261 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
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	666421: Inhibition of PHD1	ic50	0.0002	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	666421: Inhibition of PHD1	ic50	0.0002	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	1067673: Inhibition of PHD1 (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	0.0002	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	666421: Inhibition of PHD1	ic50	0.0002	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	666421: Inhibition of PHD1	ic50	0.0002	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	666421: Inhibition of PHD1	ic50	0.0002	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	666421: Inhibition of PHD1	ic50	0.0002	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	666421: Inhibition of PHD1	ic50	0.0002	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	666421: Inhibition of PHD1	ic50	0.0003	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	666421: Inhibition of PHD1	ic50	0.0003	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	666421: Inhibition of PHD1	ic50	0.0003	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	666421: Inhibition of PHD1	ic50	0.0003	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]-N-methylbenzamide	666421: Inhibition of PHD1	ic50	0.0003	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	666421: Inhibition of PHD1	ic50	0.0003	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	666421: Inhibition of PHD1	ic50	0.0003	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	666421: Inhibition of PHD1	ic50	0.0003	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	666421: Inhibition of PHD1	ic50	0.0004	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	666421: Inhibition of PHD1	ic50	0.0004	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	666421: Inhibition of PHD1	ic50	0.0004	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	666421: Inhibition of PHD1	ic50	0.0004	uM
3-methyl-4-[5-[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]-2-pyridinyl]benzoic acid	666421: Inhibition of PHD1	ic50	0.0005	uM
8-[(3-methyl-2-pyridinyl)methyl]-3-[4-(4-morpholin-4-ylphenyl)phenyl]-1-(6-oxo-1H-pyrimidin-4-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0005	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]benzamide	666421: Inhibition of PHD1	ic50	0.0007	uM
1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-3-[4-[4-(5-oxo-1,2-dihydropyrazol-3-yl)phenyl]phenyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0008	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	666421: Inhibition of PHD1	ic50	0.0008	uM
3-chloro-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	666421: Inhibition of PHD1	ic50	0.0009	uM
N-[bis(4-methoxyphenyl)methyl]-6-oxo-2-pyridazin-3-yl-1H-pyrimidine-5-carboxamide	1735053: Inhibition of FLAG-tagged full-length HIF-PHD1 (unknown origin) expressed in baculovirus infected Sf9 cells using 2-oxoglutarate and HIF1alpha biotinyl-DLDLEMLAPYIPMDDDFQL as peptide substrates preincubated for 30 mins followed by substrate addition and measured after 2 hrs by LANCE assay	ic50	0.0010	uM
3-methyl-4-[5-[8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-pyrazin-2-yl-1,3,8-triazaspiro[4.5]decan-3-yl]-2-pyridinyl]benzoic acid	666421: Inhibition of PHD1	ic50	0.0010	uM
3-methyl-4-[5-[8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-pyrimidin-4-yl-1,3,8-triazaspiro[4.5]decan-3-yl]-2-pyridinyl]benzoic acid	666421: Inhibition of PHD1	ic50	0.0010	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	666421: Inhibition of PHD1	ic50	0.0011	uM
4-[5-[1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]-2-pyridinyl]benzoic acid	666421: Inhibition of PHD1	ic50	0.0011	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]benzonitrile	666421: Inhibition of PHD1	ic50	0.0011	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	666421: Inhibition of PHD1	ic50	0.0011	uM
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	666421: Inhibition of PHD1	ic50	0.0012	uM
2-chloro-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	666421: Inhibition of PHD1	ic50	0.0012	uM
8-[(3-methyl-2-pyridinyl)methyl]-1-(6-oxo-1H-pyrimidin-4-yl)-3-(4-phenylphenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0013	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	1533128: Inhibition of recombinant human HIF-PHD1 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	0.0014	uM
8-[(3-methyl-2-pyridinyl)methyl]-1-(2-oxo-1H-pyrimidin-6-yl)-3-(4-phenylphenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0014	uM
8-[(3-methyl-2-pyridinyl)methyl]-1-(6-oxo-1H-pyridin-2-yl)-3-(4-phenylphenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0014	uM
8-[(3-methyl-2-pyridinyl)methyl]-1-(4-oxo-1H-pyridin-2-yl)-3-(4-phenylphenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0014	uM
4-[5-[1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]-2-pyridinyl]-3-methylbenzoic acid	666421: Inhibition of PHD1	ic50	0.0016	uM
8-[(3-methyl-2-pyridinyl)methyl]-3-(4-phenylphenyl)-1-pyrimidin-2-yl-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0017	uM
8-[(3-methyl-2-pyridinyl)methyl]-1-(6-oxo-1H-pyrimidin-2-yl)-3-(4-phenylphenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0018	uM
3-[4-(3H-benzimidazol-5-yl)phenyl]-1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0018	uM
3-(4-cyclohexylphenyl)-8-[(3-methyl-2-pyridinyl)methyl]-1-(6-oxo-1H-pyrimidin-4-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0019	uM
8-[(3-methyl-2-pyridinyl)methyl]-1-(6-oxo-1H-pyrimidin-4-yl)-3-[4-(2-oxo-1H-pyrimidin-5-yl)phenyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0020	uM
2-[[10-hydroxy-12-oxo-2-(1,3-thiazol-5-yl)-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5,7,9(13),10-tetraene-11-carbonyl]amino]acetic acid	1533128: Inhibition of recombinant human HIF-PHD1 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	0.0021	uM
8-[(3-methyl-2-pyridinyl)methyl]-1-(6-oxo-1H-pyridazin-3-yl)-3-(4-phenylphenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0021	uM
3-[4-(1H-indazol-6-yl)phenyl]-1-(6-methoxypyrimidin-4-yl)-8-[(3-methyl-2-pyridinyl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione	666421: Inhibition of PHD1	ic50	0.0021	uM
2-[[1-[(4-chlorophenyl)methyl]-4-hydroxy-2-oxo-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl]amino]acetic acid	1533128: Inhibition of recombinant human HIF-PHD1 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	0.0021	uM

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Smoke	decreases expression, increases abundance	2
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
cobaltous chloride	decreases expression	1
1,10-phenanthroline	decreases expression	1
cobalt sulfate	decreases expression	1
dinophysistoxin 1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
5-n-butyl-pyrazolo(1,5-a)pyrimidine	affects binding	1
Zoledronic Acid	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzene	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Calcitriol	increases expression, affects cotreatment	1
Cisplatin	decreases expression	1
Clioquinol	decreases expression	1
Lipopolysaccharides	decreases reaction, increases expression	1
Testosterone	affects cotreatment, increases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Vitamin E	increases expression	1

ChEMBL screening assays

31 unique, capped per target: 31 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1219076	Binding	Inhibition of human recombinant PHD1 expressed in Sf9 cells by time-resolved fluorescence assay	Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone demethylase inhibitors. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9E2	Ubigene HEK293 EGLN2 KO	Transformed cell line	Female
CVCL_E1VW	HAP1 EGLN2 (-) 2	Cancer cell line	Male
CVCL_XN37	HAP1 EGLN2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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