HIF1A

Summary

HIF1A (hypoxia inducible factor 1 subunit alpha, HGNC:4910) is a protein-coding gene on chromosome 14q23.2, encoding Hypoxia-inducible factor 1-alpha (Q16665). Functions as a master transcriptional regulator of the adaptive response to hypoxia. In precision oncology, HIF1A EXPRESSION confers sensitivity to Pazopanib in Renal Cell Carcinoma (CIViC Level B).

This gene encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1), which is a heterodimer composed of an alpha and a beta subunit. HIF-1 functions as a master regulator of cellular and systemic homeostatic response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis, apoptosis, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. HIF-1 thus plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.

Source: NCBI Gene 3091 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 135 total — 2 pathogenic, 4 likely-pathogenic
• Druggable target: yes — 255 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Transcription factor: yes — 504 downstream targets (CollecTRI)
• MANE Select transcript: NM_001530

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4910
Approved symbol	HIF1A
Name	hypoxia inducible factor 1 subunit alpha
Location	14q23.2
Locus type	gene with protein product
Status	Approved
Aliases	MOP1, HIF-1alpha, PASD8, HIF1, bHLHe78
Ensembl gene	ENSG00000100644
Ensembl biotype	protein_coding
OMIM	603348
Entrez	3091

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 20 protein_coding, 6 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000323441, ENST00000337138, ENST00000394997, ENST00000539097, ENST00000547430, ENST00000553999, ENST00000555014, ENST00000556237, ENST00000556827, ENST00000557206, ENST00000557446, ENST00000557538, ENST00000908731, ENST00000908732, ENST00000918842, ENST00000918843, ENST00000918844, ENST00000918845, ENST00000918846, ENST00000918847, ENST00000918848, ENST00000918849, ENST00000918850, ENST00000918851, ENST00000941079, ENST00000941080, ENST00000941081, ENST00000941082

RefSeq mRNA: 3 — MANE Select: NM_001530 NM_001243084, NM_001530, NM_181054

CCDS: CCDS9753, CCDS9754

Canonical transcript exons

ENST00000337138 — 15 exons

Exon	Start	End
ENSE00000658284	61727453	61727655
ENSE00000658285	61732418	61732524
ENSE00000658287	61736889	61737109
ENSE00000658289	61738087	61738373
ENSE00000658291	61740505	61740627
ENSE00000658295	61744705	61744813
ENSE00000658297	61745691	61745817
ENSE00003467508	61746934	61748258
ENSE00003474252	61721509	61721654
ENSE00003506980	61734138	61734285
ENSE00003509800	61740755	61741188
ENSE00003533403	61721739	61721823
ENSE00003592584	61720382	61720572
ENSE00003673401	61726706	61726818
ENSE00003844156	61695513	61695839

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 242.6376 / max 5013.4992, expressed in 1827 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139985	198.7084	1826
139986	17.6974	1704
139984	8.9634	1731
139987	8.9291	1535
140000	2.0425	968
207251	1.5509	883
140007	1.1913	639
140006	1.1004	531
139997	0.9032	508
207250	0.3410	132

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	99.61	gold quality
epithelial cell of pancreas	CL:0000083	99.54	gold quality
corpus epididymis	UBERON:0004359	99.54	gold quality
caput epididymis	UBERON:0004358	99.49	gold quality
tibia	UBERON:0000979	99.48	gold quality
cartilage tissue	UBERON:0002418	99.48	gold quality
gingival epithelium	UBERON:0001949	99.42	gold quality
visceral pleura	UBERON:0002401	99.38	gold quality
seminal vesicle	UBERON:0000998	99.33	gold quality
gingiva	UBERON:0001828	99.33	gold quality
cauda epididymis	UBERON:0004360	99.33	gold quality
epithelium of nasopharynx	UBERON:0001951	99.18	gold quality
lower lobe of lung	UBERON:0008949	99.16	gold quality
tongue squamous epithelium	UBERON:0006919	99.15	gold quality
pleura	UBERON:0000977	99.14	gold quality
germinal epithelium of ovary	UBERON:0001304	99.11	gold quality
endothelial cell	CL:0000115	99.10	gold quality
parietal pleura	UBERON:0002400	99.02	gold quality
gall bladder	UBERON:0002110	98.93	gold quality
type B pancreatic cell	CL:0000169	98.91	gold quality
adrenal tissue	UBERON:0018303	98.88	gold quality
oral cavity	UBERON:0000167	98.87	gold quality
islet of Langerhans	UBERON:0000006	98.85	gold quality
hair follicle	UBERON:0002073	98.82	gold quality
renal medulla	UBERON:0000362	98.81	gold quality
choroid plexus epithelium	UBERON:0003911	98.80	gold quality
squamous epithelium	UBERON:0006914	98.77	gold quality
pericardium	UBERON:0002407	98.74	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.74	gold quality
vena cava	UBERON:0004087	98.72	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	63.01
E-MTAB-9221	yes	25.69
E-CURD-112	yes	14.57
E-HCAD-13	yes	12.64
E-CURD-46	yes	12.17
E-MTAB-7249	no	9174.98
E-CURD-89	no	1677.81
E-MTAB-7303	no	800.78
E-MTAB-7606	no	211.18
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

504 targets.

Target	Regulation
ABCA1	Unknown
ABCB1	Repression
ABCC8
ABCC9	Activation
ABCG2	Unknown
ABL1
ACAN
ACE	Activation
ACE2	Repression
ACKR3	Activation
ADAM17	Unknown
ADAM2
ADIPOQ	Activation
ADM	Activation
ADM2	Activation
ADORA2B	Unknown
AFP
AGT	Activation
AGTR1	Activation
AKT1
ALAS2	Activation
ALDOA	Activation
ALOX5AP	Unknown
ANG	Activation
ANGPT1	Repression
ANGPT2	Activation
ANGPT4	Activation
ANGPTL4	Unknown
ANKRD37	Unknown
APC	Repression

JASPAR motifs

Motif	Name	Family
MA0259.1	ARNT::HIF1A	PAS domain factors
MA0259.2	ARNT::HIF1A	PAS domain factors
MA1106.1	HIF1A	PAS domain factors
MA1106.2	HIF1A	PAS domain factors

JASPAR matrix evidence (PMIDs): PMID:16234508, PMID:20061373

Upstream regulators (CollecTRI, top): ARNT, ATF2, BMAL1, BRCA1, CREB1, CTNNB1, EGR1, EPAS1, FOXO3, FOXO4, HDAC7, HIF1A, HIF3A, HIPK2, HSF2, HSF4, IRF6, KLF2, KLF5, KMT2A, LIMD1, MEIS1, MITF, MT3, MTA1, MYC, NFE2L2, NFKB1, NFKB2, NFKB, PROX1, RARB, RELA, RORA, RXRA, SIM2, SIRT1, SP1, STAT3, TEAD4

miRNA regulators (miRDB)

156 targeting HIF1A, 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-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-7-1-3P	99.91	71.53	4384

Literature-anchored findings (GeneRIF, showing 40)

• hypoxic induction of the COOH-terminal transactivation domain (CAD) occurs through abrogation of hydroxylation of a conserved asparagine in the CAD (PMID:11823643)
• Normoxic induction of the hypoxia-inducible factor 1alpha by insulin and interleukin-1beta involves the phosphatidylinositol 3-kinase pathway. (PMID:11852072)
• Repression of alpha-fetoprotein gene expression under hypoxic conditions in human hepatoma cells: characterization of a negative hypoxia response element that mediates opposite effects of hypoxia inducible factor-1 and c-Myc. (PMID:11861398)
• Review. HIF-1alpha is overexpressed in many human cancers and this correlates with disease severity. It controls expression of genes associated with angiogenesis and hypoxia resistance. (PMID:11868612)
• Stabilization of hypoxia-inducible factor-1alpha is involved in the hypoxic stimuli-induced expression of vascular endothelial growth factor in osteoblastic cells (PMID:11886167)
• carboxyl-terminal transactivation activity of hypoxia-inducible factor 1 alpha is governed by a von Hippel-Lindau protein-independent, hydroxylation-regulated association with p300/CBP (PMID:11940656)
• up-regulates a series of genes involved in aerobic glycolysis during carcinogenesis (PMID:11943784)
• activation of HIF-1 is modulated by cytochrome P-450 reductase in cell membrane (PMID:11971899)
• Overexpression of HIF-1alpha and HIF-2alpha was demonstrated in three HNSCC cell lines under hypoxia and tumor tissue versus normal tissue (n = 20, HIF-1alpha, P = 0.023; HIF-2alpha, P = 0.013). (PMID:11980639)
• Melphalan availability in hypoxia-inducible factor-1alpha+/+ and factor-1alpha-/- tumors is independent of tumor vessel density and correlates with melphalan erythrocyte transport (PMID:11992540)
• structure of an HIF-1alpha-pVHL complex determined; role of hydroxyproline (PMID:12004076)
• modulation of synthesis by sodium butyrate in colon cancer cell line HT29 (PMID:12016145)
• Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family (PMID:12042299)
• crystal structure and basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. (PMID:12050673)
• Inhibitors of mitochondrial complex I attenuate the accumulation of hypoxia-inducible factor-1 during hypoxia in Hep3B cells. (PMID:12062197)
• Induction of leptin gene expression by hypoxia and HIF1. (PMID:12084725)
• HIF-1alpha-prolyl hydroxylase: molecular target of nitric oxide in the hypoxic signal transduction pathway (PMID:12099689)
• enzymatic hydroxylation of a conserved prolyl residue in hypoxia-inducible factor alpha subunits governs capture by the pVHL E3 ubiquitin ligase complex (PMID:12123724)
• two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53 (PMID:12124396)
• Human hormone-refractory prostate cancers can harbor mutations in the O(2)-dependent degradation domain. (PMID:12136249)
• Data show that exposure of human colon carcinoma cells to insulin-like growth factor-1 (IGF-1) induces the expression of HIF-1 alpha, the regulated subunit of hypoxia-inducible factor 1, a known transactivator of the VEGF gene. (PMID:12149254)
• Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1 alpha stabilization: a role for phosphatidylinositol 3’-kinase. (PMID:12154057)
• REVIEW: Hydroxylation of specific residues in the alpha subunit of HIF by a series of non-haem iron-dependent dioxygenases as a novel mechanism of protein modification that transduces the oxygen-sensitive signal for transcription of erythropoietin (PMID:12207089)
• HIF-1alpha expression related to increased angiogenesis in endometrial adenocarcinoma (PMID:12209691)
• In human cancer cells, both intratumoral hypoxia and genetic alterations affecting signal transduction pathways lead to increased HIF-1 activity, which promotes angiogenesis, metabolic adaptation, and other critical aspects of tumor progression. (PMID:12213597)
• These results suggest that the expression of HIF-1 and VEGF induced by Cr(VI) may be an important signaling pathway in the Cr(VI)-induced carcinogenesis. (PMID:12213806)
• transactivates the human leptin gene promoter (PMID:12215445)
• HIF-1 binds to Sp1 and regulates basal endoglin transcription in human and mammalian cells (PMID:12228247)
• results indicate that mitochondria-derived reactive oxygen species generated in response to hypoxia and increased accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) are not necessary for oxygen sensing in HeLa cells (PMID:12237125)
• Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin (PMID:12242281)
• Expression of hypoxia inducible factor-1 alpha and correlation with preoperative embolization of meningiomas. (PMID:12296651)
• The binding of pVHL to HIF is governed by the enzymatic hydroxylation of conserved prolyl residues within peptidic motifs present in the HIFalpha family members. (PMID:12351678)
• Hypoxic but not anoxic stabilization requires mitochondrial reactive oxygen species (PMID:12376345)
• HIF-1alpha is regulated by hypoxia through a PGE(2)-COX-2-catalyzed pathway in human tumor cells (PMID:12401798)
• autocrine regulation of TGF-beta2 production in endothelial cell hypoxia may involve cross-talk between Smad3 and hypoxia inducible factor-1alpha signaling pathways (PMID:12411310)
• HIF-1 alpha is correlated with apoptosis, but has no relationship with proliferation. (PMID:12451989)
• HIF-1alpha is regulated and destabilized by ARD-1 mediated acetylation. (PMID:12464182)
• HIF-1alpha is regulated by the von Hippel-Lindau tumor suppressor gene product (PMID:12468553)
• HIF-1 binds to FIH-1 in a specific binding site (PMID:12482756)
• HIF-1alpha is activated by p38, but it does not mediate induction of VEGF mRNA (PMID:12482858)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	hif1ab	ENSDARG00000034293
mus_musculus	Hif1a	ENSMUSG00000021109
rattus_norvegicus	Hif1a	ENSRNOG00000008292
drosophila_melanogaster	trh	FBGN0262139
drosophila_melanogaster	sima	FBGN0266411
caenorhabditis_elegans		WBGENE00001851

Paralogs (7): SIM1 (ENSG00000112246), EPAS1 (ENSG00000116016), HIF3A (ENSG00000124440), NPAS1 (ENSG00000130751), NPAS3 (ENSG00000151322), SIM2 (ENSG00000159263), NPAS4 (ENSG00000174576)

Protein

Protein identifiers

Hypoxia-inducible factor 1-alpha — Q16665 (reviewed: Q16665)

Alternative names: ARNT-interacting protein, Basic-helix-loop-helix-PAS protein MOP1, Class E basic helix-loop-helix protein 78, Member of PAS protein 1, PAS domain-containing protein 8

All UniProt accessions (3): Q16665, A8MYV6, D0VY79

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5’-TACGTG-3’ within the hypoxia response element (HRE) of target gene promoters. Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300. Activity is enhanced by interaction with NCOA1 and/or NCOA2. Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia. (Microbial infection) Upon infection by human coronavirus SARS-CoV-2, is required for induction of glycolysis in monocytes and the consequent pro-inflammatory state. In monocytes, induces expression of ACE2 and cytokines such as IL1B, TNF, IL6, and interferons. Promotes human coronavirus SARS-CoV-2 replication and monocyte inflammatory response.

Subunit / interactions. Interacts with the ARNT; forms a heterodimer that binds core DNA sequence 5’-TACGTG-3’ within the hypoxia response element (HRE) of target gene promoters. Interacts with COPS5; the interaction increases the transcriptional activity of HIF1A through increased stability. Interacts with EP300 (via TAZ-type 1 domains); the interaction is stimulated in response to hypoxia and inhibited by CITED2. Interacts with CREBBP (via TAZ-type 1 domains). Interacts with NCOA1, NCOA2, APEX1 and HSP90. Interacts (hydroxylated within the ODD domain) with VHLL (via beta domain); the interaction, leads to polyubiquitination and subsequent HIF1A proteasomal degradation. During hypoxia, sumoylated HIF1A also binds VHL; the interaction promotes the ubiquitination of HIF1A. Interacts with SENP1; the interaction desumoylates HIF1A resulting in stabilization and activation of transcription. Interacts (via the ODD domain) with NAA10; the interaction appears not to acetylate HIF1A nor have any affect on protein stability, during hypoxia. Interacts with RWDD3; the interaction enhances HIF1A sumoylation. Interacts with TSGA10. Interacts with HIF3A. Interacts with RORA (via the DNA binding domain); the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interaction with PSMA7 inhibits the transactivation activity of HIF1A under both normoxic and hypoxia-mimicking conditions. Interacts with USP20. Interacts with RACK1; promotes HIF1A ubiquitination and proteasome-mediated degradation. Interacts (via N-terminus) with USP19. Interacts with SIRT2. Interacts (deacetylated form) with EGLN1. Interacts with CBFA2T3. Interacts with HSP90AA1 and HSP90AB1. Interacts with DCUN1D1; this interaction increases the interaction between VHL and DCUN1D1. Interacts with HIF1AN.

Subcellular location. Cytoplasm. Nucleus. Nucleus speckle.

Tissue specificity. Expressed in most tissues with highest levels in kidney and heart. Overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors. A higher level expression seen in pituitary tumors as compared to the pituitary gland.

Post-translational modifications. S-nitrosylation of Cys-800 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex. Requires phosphorylation for DNA-binding. Phosphorylation at Ser-247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding. Phosphorylation by GSK3-beta and PLK3 promote degradation by the proteasome. Sumoylated; with SUMO1 under hypoxia. Sumoylation is enhanced through interaction with RWDD3. Both sumoylation and desumoylation seem to be involved in the regulation of its stability during hypoxia. Sumoylation can promote either its stabilization or its VHL-dependent degradation by promoting hydroxyproline-independent HIF1A-VHL complex binding, thus leading to HIF1A ubiquitination and proteasomal degradation. Desumoylation by SENP1 increases its stability amd transcriptional activity. There is a disaccord between various publications on the effect of sumoylation and desumoylation on its stability and transcriptional activity. Acetylation of Lys-532 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation. Deacetylation of Lys-709 by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation. Polyubiquitinated; in normoxia, following hydroxylation and interaction with VHL. Lys-532 appears to be the principal site of ubiquitination. Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination through preventing hydroxylation at Asn-803. Ubiquitinated by E3 ligase VHL. Deubiquitinated by UCHL1. In normoxia, is hydroxylated on Pro-402 and Pro-564 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1. EGLN3/PHD3 has also been shown to hydroxylate Pro-564. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Deubiquitinated by USP20. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization. In normoxia, is hydroxylated on Asn-803 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. This hydroxylation is inhibited by the Cu/Zn-chelator, Clioquinol. Repressed by iron ion, via Fe(2+) prolyl hydroxylase (PHD) enzymes-mediated hydroxylation and subsequent proteasomal degradation. The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains. (Microbial infection) Glycosylated at Arg-18 by enteropathogenic E.coli protein NleB1: arginine GlcNAcylation enhances transcription factor activity and impairs glucose metabolism.

Activity regulation. Induced by reactive oxygen species (ROS). (Microbial infection) In monocytes, human coronavirus SARS-CoV-2 increases HIF1A levels and activity which promotes a pro-inflammatory state.

Domain organisation. Contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID).

Induction. Under reduced oxygen tension. Induced also by various receptor-mediated factors such as growth factors, cytokines, and circulatory factors such as PDGF, EGF, FGF2, IGF2, TGFB1, HGF, TNF, IL1B/interleukin-1 beta, angiotensin-2 and thrombin. However, this induction is less intense than that stimulated by hypoxia. Repressed by HIPK2 and LIMD1.

Miscellaneous. Up-regulated in peripheral T-lymphocytes after T-cell receptor stimulation. Highest expression in peripheral blood leukocytes and thymus.

Isoforms (3)

UniProt ID	Names	Canonical?
Q16665-1	1	yes
Q16665-2	2
Q16665-3	3, I.3

RefSeq proteins (3): NP_001230013, NP_001521, NP_851397 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR001321	HIF-1_alpha	Family
IPR001610	PAC	Repeat
IPR011598	bHLH_dom	Domain
IPR013655	PAS_fold_3	Domain
IPR013767	PAS_fold	Domain
IPR014887	HIF-1_CTAD	Domain
IPR021537	HIF_alpha-like	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00989, PF08447, PF08778, PF11413, PF23171

UniProt features (97 total): mutagenesis site 29, region of interest 12, modified residue 12, helix 10, strand 8, cross-link 5, domain 4, turn 4, compositionally biased region 3, splice variant 3, sequence variant 3, chain 1, short sequence motif 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
4H6J	X-RAY DIFFRACTION	1.52
4AJY	X-RAY DIFFRACTION	1.73
6GMR	X-RAY DIFFRACTION	1.75
8HE0	X-RAY DIFFRACTION	1.8
5L9V	X-RAY DIFFRACTION	1.83
6GFX	X-RAY DIFFRACTION	1.83
1LM8	X-RAY DIFFRACTION	1.85
8HE3	X-RAY DIFFRACTION	1.9
5L9B	X-RAY DIFFRACTION	1.95
1LQB	X-RAY DIFFRACTION	2
3HQR	X-RAY DIFFRACTION	2
7QGS	X-RAY DIFFRACTION	2
7LVS	X-RAY DIFFRACTION	2.02
5JWP	X-RAY DIFFRACTION	2.1
5LAS	X-RAY DIFFRACTION	2.1
1H2K	X-RAY DIFFRACTION	2.15
1H2L	X-RAY DIFFRACTION	2.25
6YW3	X-RAY DIFFRACTION	2.28
2ILM	X-RAY DIFFRACTION	2.3
3HQU	X-RAY DIFFRACTION	2.3
1H2M	X-RAY DIFFRACTION	2.5
5LA9	X-RAY DIFFRACTION	2.81
9OFU	ELECTRON MICROSCOPY	3.9
1L3E	SOLUTION NMR
1L8C	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16665-F1	61.43	0.32

Functional residue map

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

Post-translational modifications (17): 247, 402, 532, 551, 555, 564, 576, 589, 657, 709, 800, 803, 391, 477, 532, 538, 547

Glycosylation sites (1): 18

Mutagenesis-validated functional residues (29):

Position	Phenotype
18	strongly reduced glcnacylation by e.coli nleb1.
247	constitutive kinase activity.
247	impaired kinase activity.
377	no change in hif1a protein turnover rate but increased transcriptional activity; when associated with r-391; r-477 and r
389	no change in sumoylation.
391	abolishes 1 sumoylation. abolishes 1 sumoylation; when associated with r-532. abolishes 2 sumoylations; when associated
392	no change in sumoylation.
394	no change in vhle3-dependent ubiquitination.
397	abolishes vhle3-dependent ubiquitination; when associated with a-400.
400	abolishes vhle3-dependent ubiquitination; when associated with a-397.
402	abolishes in vhle3-dependent ubiquitination, abolishes oxygen-dependent regulation of vp16, partially reduced vhle targe
442	no change in sumoylation.
460	no change in sumoylation nor in ard1-mediated acetylation.
477	abolishes 1 sumoylation. abolishes 2 sumoylations; when associated with r-391. no change in hif1a protein turnover rate
532	reduced ubiquitination. no change in sumoylation nor on interaction with naa10. no change in hif1a protein turnover rate
538	no change in sumoylation, but reduced ubiquitination. complete loss of ubiquitination, but no change in vhl binding; whe
547	no change in sumoylation, but reduced ubiquitination. complete loss of ubiquitination, but no change in vhl binding; whe
551	constitutive expression under nonhypoxic conditions by decreasing ubiquitination.
552	constitutive expression under nonhypoxic conditions by decreasing ubiquitination.
564	increases hif1a instability and reduces hif1a-induced target gene transcriptional activation; when associated with a-402
564	no change in vhl-dependent ubiquitination. partially reduced vhle target site ubiquitination. no vhle target site ubiqui
576	induces stabilization of the protein.
657	induces stabilization of the protein.
709	abolishes sirt2-mediated deacetylation, increases hif1a instability and reduces hif1a-induced target gene transcriptiona
719	dramatic reduction of accumulation in the nucleus in response to hypoxia.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-1234158	Regulation of gene expression by Hypoxia-inducible Factor
R-HSA-1234174	Cellular response to hypoxia
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-5689880	Ub-specific processing proteases
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-8849473	PTK6 Expression
R-HSA-8857538	PTK6 promotes HIF1A stabilization
R-HSA-8951664	Neddylation
R-HSA-9701898	STAT3 nuclear events downstream of ALK signaling
R-HSA-9909649	Regulation of PD-L1(CD274) transcription

MSigDB gene sets: 921 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GCACCTT_MIR18A_MIR18B, RNGTGGGC_UNKNOWN, GOBP_HEMOGLOBIN_METABOLIC_PROCESS, REACTOME_SIGNALING_BY_NOTCH, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYONIC_HEMOPOIESIS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (98): response to reactive oxygen species (GO:0000302), angiogenesis (GO:0001525), response to hypoxia (GO:0001666), intracellular glucose homeostasis (GO:0001678), neural crest cell migration (GO:0001755), epithelial to mesenchymal transition (GO:0001837), embryonic placenta development (GO:0001892), B-1 B cell homeostasis (GO:0001922), positive regulation of endothelial cell proliferation (GO:0001938), heart looping (GO:0001947), positive regulation of neuroblast proliferation (GO:0002052), chondrocyte differentiation (GO:0002062), glandular epithelial cell maturation (GO:0002071), connective tissue replacement involved in inflammatory response wound healing (GO:0002248), outflow tract morphogenesis (GO:0003151), cardiac ventricle morphogenesis (GO:0003208), lactate metabolic process (GO:0006089), regulation of glycolytic process (GO:0006110), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), intracellular iron ion homeostasis (GO:0006879), signal transduction (GO:0007165), neuroblast proliferation (GO:0007405), lactation (GO:0007595), visual learning (GO:0008542), response to iron ion (GO:0010039), regulation of gene expression (GO:0010468), vascular endothelial growth factor production (GO:0010573), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), positive regulation of epithelial cell migration (GO:0010634), response to muscle activity (GO:0014850), positive regulation of macroautophagy (GO:0016239), axonal transport of mitochondrion (GO:0019896), neural fold elevation formation (GO:0021502), cerebral cortex development (GO:0021987), bone mineralization (GO:0030282), negative regulation of bone mineralization (GO:0030502), positive regulation of vascular endothelial growth factor receptor signaling pathway (GO:0030949)

GO Molecular Function (26): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription activator activity (GO:0001216), DNA-binding transcription repressor activity (GO:0001217), transcription corepressor binding (GO:0001222), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), p53 binding (GO:0002039), DNA-binding transcription factor activity (GO:0003700), nuclear receptor binding (GO:0016922), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), protein domain specific binding (GO:0019904), ubiquitin protein ligase binding (GO:0031625), histone deacetylase binding (GO:0042826), protein heterodimerization activity (GO:0046982), Hsp90 protein binding (GO:0051879), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), E-box binding (GO:0070888), transcription regulator activator activity (GO:0140537), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), protein dimerization activity (GO:0046983)

GO Cellular Component (13): chromatin (GO:0000785), euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear body (GO:0016604), nuclear speck (GO:0016607), motile cilium (GO:0031514), protein-containing complex (GO:0032991), RNA polymerase II transcription regulator complex (GO:0090575), axon cytoplasm (GO:1904115)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Cellular response to hypoxia	2
Signaling by PTK6	2
Cellular responses to stress	1
Signaling by NOTCH1	1
Deubiquitination	1
Signaling by Interleukins	1
Post-translational protein modification	1
Signaling by ALK	1
Regulation of PD-L1(CD274) expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription cis-regulatory region binding	5
cellular anatomical structure	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
DNA-binding transcription factor activity	3
protein binding	3
regulation of DNA-templated transcription	2
chromatin	2
transcription coregulator binding	2
response to oxidative stress	1
response to oxygen-containing compound	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
response to stress	1
response to decreased oxygen levels	1
glucose homeostasis	1
intracellular chemical homeostasis	1
neural crest cell development	1
mesenchymal cell migration	1
mesenchymal cell differentiation	1
in utero embryonic development	1
placenta development	1
embryonic organ development	1
B cell homeostasis	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
cell differentiation	1
cartilage development	1
glandular epithelial cell development	1
columnar/cuboidal epithelial cell maturation	1
wound healing involved in inflammatory response	1
connective tissue replacement	1
heart morphogenesis	1
anatomical structure morphogenesis	1

Protein interactions and networks

STRING

8125 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HIF1A	VHL	P40337	998
HIF1A	EP300	Q09472	996
HIF1A	PKM	P14618	995
HIF1A	FOXO3	O43524	995
HIF1A	TP53	P04637	994
HIF1A	HSP90AA1	P07900	994
HIF1A	HSP90AB1	P08238	994
HIF1A	CREBBP	Q92793	991
HIF1A	ARNT	P27540	991
HIF1A	CTNNB1	P35222	989
HIF1A	FOXP3	Q9BZS1	988
HIF1A	ELOC	Q15369	987
HIF1A	XBP1	P17861	985
HIF1A	RELA	Q04206	985
HIF1A	EPAS1	Q99814	984
HIF1A	ARNT2	Q9HBZ2	984

IntAct

327 interactions, top by confidence:

A	B	Type	Score
HIF1A	VHL	psi-mi:“MI:0914”(association)	0.970
HIF1A	VHL	psi-mi:“MI:0915”(physical association)	0.970
VHL	HIF1A	psi-mi:“MI:0407”(direct interaction)	0.970
VHL	HIF1A	psi-mi:“MI:0915”(physical association)	0.970
EP300	HIF1A	psi-mi:“MI:0915”(physical association)	0.960
HIF1A	EP300	psi-mi:“MI:0915”(physical association)	0.960
HIF1A	EP300	psi-mi:“MI:0914”(association)	0.960
HIF1A	ARNT	psi-mi:“MI:0915”(physical association)	0.940
ARNT	HIF1A	psi-mi:“MI:0407”(direct interaction)	0.940
ARNT	HIF1A	psi-mi:“MI:0915”(physical association)	0.940
HIF1A	ARNT	psi-mi:“MI:0914”(association)	0.940
HIF1A	HIF1AN	psi-mi:“MI:0407”(direct interaction)	0.920
HIF1AN	HIF1A	psi-mi:“MI:0407”(direct interaction)	0.920
HIF1AN	HIF1A	psi-mi:“MI:0210”(hydroxylation reaction)	0.920
EGLN3	HIF1A	psi-mi:“MI:0915”(physical association)	0.920

BioGRID (1282): HIF1A (Biochemical Activity), HSP90AA1 (Affinity Capture-Western), VHL (Affinity Capture-Western), EP300 (Affinity Capture-Western), HIF1A (Affinity Capture-Western), HIF1A (Reconstituted Complex), EP300 (Reconstituted Complex), EP300 (Two-hybrid), HIF1A (Affinity Capture-Western), EP300 (Affinity Capture-Western), EP300 (Affinity Capture-Western), SENP3 (Affinity Capture-Western), HIF1A (Biochemical Activity), EP300 (Reconstituted Complex), EGLN3 (Two-hybrid)

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

Diamond homologs: A1YFY6, A2T6X9, A9YTQ3, O09000, O35800, P05709, P81133, P97459, P97481, Q0PGG7, Q0VBL6, Q14190, Q16665, Q24119, Q24167, Q309Z6, Q61045, Q61079, Q61221, Q8IXF0, Q98SJ5, Q98SW2, Q99742, Q99814, Q9I8A9, Q9JHS1, Q9JHS2, Q9QZQ0, Q9XTA5, Q9Y2N7, Q9YIB9, G5EGD2, O02747, P30561, P35869, P41738, Q8R4S2, Q8R4S4, Q8R4S5, Q8R4S6

SIGNOR signaling

81 interactions.

A	Effect	B	Mechanism
NOTCH1	“up-regulates activity”	HIF1A	relocalization
MAPK14	up-regulates	HIF1A
SIAH2	up-regulates	HIF1A
RWDD3	up-regulates	HIF1A	sumoylation
SENP1	up-regulates	HIF1A	desumoylation
mTORC1	up-regulates	HIF1A
CSNK1D	down-regulates	HIF1A	phosphorylation
ATM	up-regulates	HIF1A	phosphorylation
MAPK1	up-regulates	HIF1A	phosphorylation
MAPK3	up-regulates	HIF1A	phosphorylation
PLK3	down-regulates	HIF1A	phosphorylation
RBPJ/NOTCH	“up-regulates quantity by expression”	HIF1A	“transcriptional regulation”
HIF1A	“up-regulates quantity by expression”	CCL2	“transcriptional regulation”
HIF1A	“up-regulates quantity by expression”	ABCB1	“transcriptional regulation”
HIF1A	“up-regulates quantity by expression”	ALAS2	“transcriptional regulation”
HIF1A	“up-regulates quantity by expression”	ALDOA	“transcriptional regulation”
HIF1A	“up-regulates quantity by expression”	NT5E	“transcriptional regulation”
HIF1A	“up-regulates quantity by expression”	PGK1	“transcriptional regulation”
DAB2IP	“down-regulates quantity by destabilization”	HIF1A
PROX1	“up-regulates quantity by stabilization”	HIF1A
HIF1A	up-regulates	Epithelial-mesenchymal_transition
HIF1A	up-regulates	Metabolism
HIF1A	“up-regulates quantity”	VEGFA	“transcriptional regulation”
HIF1A	“up-regulates quantity”	EPO	“transcriptional regulation”
HIF1A	“up-regulates quantity by expression”	CD274	“transcriptional regulation”
EML4-ALK	“up-regulates quantity by expression”	HIF1A	“transcriptional regulation”
EML4-ALK	“up-regulates quantity by stabilization”	HIF1A

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of intracellular receptors	5	29.0×	7e-05
SUMOylation of transcription cofactors	6	25.1×	2e-05
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	7	23.8×	5e-06
NOTCH1 Intracellular Domain Regulates Transcription	5	20.5×	2e-04
Constitutive Signaling by NOTCH1 PEST Domain Mutants	5	17.0×	3e-04
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	5	17.0×	3e-04
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	6	15.2×	1e-04
KEAP1-NFE2L2 pathway	7	14.5×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	8	37.5×	1e-08
negative regulation of cell growth	6	13.9×	3e-04
response to hypoxia	9	13.9×	3e-06
cellular response to insulin stimulus	5	13.7×	1e-03
cellular response to hypoxia	7	13.7×	8e-05
positive regulation of canonical Wnt signaling pathway	5	12.5×	2e-03
in utero embryonic development	8	9.3×	2e-04
protein stabilization	8	8.6×	3e-04

Disease & clinical

Cancer significance

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

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	80
Likely benign	12
Benign	8

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2685487	GRCh37/hg19 14q22.3-23.2(chr14:55667390-64447598)x1	Pathogenic
988324	NM_001530.4(HIF1A):c.293G>A (p.Gly98Asp)	Pathogenic
1803802	NM_001530.4(HIF1A):c.1892G>A (p.Arg631His)	Likely pathogenic
1803803	NM_001530.4(HIF1A):c.1961C>T (p.Ala654Val)	Likely pathogenic
1803804	NM_001530.4(HIF1A):c.2075C>G (p.Ser692Cys)	Likely pathogenic
1803805	NM_001530.4(HIF1A):c.1369G>A (p.Glu457Lys)	Likely pathogenic

SpliceAI

1937 predictions. Top by Δscore:

Variant	Effect	Δscore
14:61695836:AAAAG:A	donor_loss	1.0000
14:61695837:AAAGT:A	donor_loss	1.0000
14:61695838:AA:A	donor_gain	1.0000
14:61695840:G:GG	donor_gain	1.0000
14:61719163:GAT:G	donor_gain	1.0000
14:61720366:T:TA	acceptor_gain	1.0000
14:61720369:T:A	acceptor_gain	1.0000
14:61720372:T:TA	acceptor_gain	1.0000
14:61720377:A:AG	acceptor_gain	1.0000
14:61720377:AGTAG:A	acceptor_gain	1.0000
14:61720378:G:GG	acceptor_gain	1.0000
14:61720378:GT:G	acceptor_gain	1.0000
14:61720378:GTA:G	acceptor_gain	1.0000
14:61720378:GTAGG:G	acceptor_gain	1.0000
14:61720380:AG:A	acceptor_gain	1.0000
14:61720381:G:T	acceptor_loss	1.0000
14:61720381:GG:G	acceptor_gain	1.0000
14:61720381:GGAT:G	acceptor_gain	1.0000
14:61720381:GGATA:G	acceptor_gain	1.0000
14:61721495:T:A	acceptor_gain	1.0000
14:61721497:T:TA	acceptor_gain	1.0000
14:61721504:TTTA:T	acceptor_loss	1.0000
14:61721507:A:AG	acceptor_gain	1.0000
14:61721507:AG:A	acceptor_gain	1.0000
14:61721507:AGGT:A	acceptor_gain	1.0000
14:61721508:G:A	acceptor_gain	1.0000
14:61721508:G:GG	acceptor_gain	1.0000
14:61721508:GGT:G	acceptor_gain	1.0000
14:61721508:GGTG:G	acceptor_gain	1.0000
14:61721508:GGTGA:G	acceptor_gain	1.0000

AlphaMissense

5490 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:61720423:C:A	A26D	1.000
14:61720426:G:C	R27T	1.000
14:61720427:A:C	R27S	1.000
14:61720427:A:T	R27S	1.000
14:61720432:G:C	R29P	1.000
14:61720435:G:C	R30P	1.000
14:61720465:T:A	L40H	1.000
14:61720465:T:C	L40P	1.000
14:61720477:T:C	L44S	1.000
14:61720509:G:C	D55H	1.000
14:61720510:A:C	D55A	1.000
14:61720510:A:T	D55V	1.000
14:61720512:A:C	K56Q	1.000
14:61720514:G:C	K56N	1.000
14:61720514:G:T	K56N	1.000
14:61720518:T:C	S58P	1.000
14:61720528:G:C	R61T	1.000
14:61720528:G:T	R61M	1.000
14:61720529:G:C	R61S	1.000
14:61720529:G:T	R61S	1.000
14:61720531:T:C	L62P	1.000
14:61721746:T:C	L127P	1.000
14:61721752:G:A	G129E	1.000
14:61726757:G:C	R170T	1.000
14:61726757:G:T	R170I	1.000
14:61726758:A:C	R170S	1.000
14:61726758:A:T	R170S	1.000
14:61726813:T:A	W189R	1.000
14:61726813:T:C	W189R	1.000
14:61727612:A:C	S244R	1.000

dbSNP variants (sampled 300 via entrez): RS1000043301 (14:61735471 C>A,T), RS1000117098 (14:61741812 A>C), RS1000126254 (14:61695702 C>T), RS1000142181 (14:61699364 A>C,T), RS1000290220 (14:61744256 TG>T), RS1000351887 (14:61747656 C>A,T), RS1000442305 (14:61707579 A>G), RS1000453797 (14:61707426 A>G), RS1000464543 (14:61694626 C>T), RS1000470194 (14:61710353 A>T), RS1000493978 (14:61695031 G>A), RS1000566287 (14:61740169 T>C), RS1000573391 (14:61746134 G>C), RS1000657784 (14:61711754 G>A), RS1000721238 (14:61699589 T>A,C)

Disease associations

OMIM: gene MIM:603348 | disease phenotypes: MIM:614569, MIM:166000

GenCC curated gene-disease

Mondo (4): prostate cancer (MONDO:0008315), Maffucci syndrome (MONDO:0013808), Ollier disease (MONDO:0008145), cholangiocarcinoma (MONDO:0019087)

Orphanet (4): Familial prostate cancer (Orphanet:1331), Maffucci syndrome (Orphanet:163634), Ollier disease (Orphanet:296), Cholangiocarcinoma (Orphanet:70567)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018281	Cholangiocarcinoma	C04.557.470.200.025.450
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL2221345 (PROTEIN FAMILY), CHEMBL3885588 (PROTEIN COMPLEX), CHEMBL4261 (SINGLE PROTEIN), CHEMBL4296108 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296117 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

255 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,043,369 (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
CHEMBL50588	EMETINE	4	22,457
CHEMBL53463	DOXORUBICIN	4	314,282
CHEMBL84	TOPOTECAN	4	141,586
CHEMBL1002	LEVOSALBUTAMOL	4	27,028
CHEMBL1009	LEVODOPA	4	103,854
CHEMBL1018	DIENESTROL	4	5,607
CHEMBL103	PROGESTERONE	4	162,141
CHEMBL1034	DICLOFENAC SODIUM	4	45,460
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1072	BUMETANIDE	4	22,087
CHEMBL1075	MORICIZINE	4	3,860
CHEMBL1091	HYDROCORTISONE ACETATE	4	45,061
CHEMBL110691	CHLORMADINONE ACETATE	4	9,747
CHEMBL1108	DROPERIDOL	4	16,888
CHEMBL1113	AMOXAPINE	4	20,128
CHEMBL1148	TORSEMIDE	4	15,151
CHEMBL1152	PREDNISOLONE ACETATE	4	12,111
CHEMBL1200	BENOXINATE	4	6,712
CHEMBL1200326	NICARDIPINE HYDROCHLORIDE	4	3,903
CHEMBL1200339	PHENYLEPHRINE HYDROCHLORIDE	4	8,981
CHEMBL1200348	SULCONAZOLE NITRATE	4
CHEMBL1200467	HYDROXYZINE PAMOATE	4
CHEMBL1200471	PYRITHIONE ZINC	4
CHEMBL1200495	HYDROCORTISONE SODIUM SUCCINATE	4
CHEMBL1200545	DIFLORASONE DIACETATE	4
CHEMBL1200560	GUANABENZ ACETATE	4
CHEMBL1200562	HYDROCORTISONE VALERATE	4
CHEMBL1200600	FLUOROMETHOLONE	4
CHEMBL1200732	AMCINONIDE	4
CHEMBL1200750	PROMETHAZINE HYDROCHLORIDE	4

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items; also 3 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
HIF1A EXPRESSION	Pazopanib	Renal Cell Carcinoma	Sensitivity/Response	CIViC B	EID1674

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11549465	Efficacy	3	axitinib;sorafenib

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11549467	HIF1A		0.00	0
rs11549465	HIF1A	3	2.75	1	axitinib;sorafenib

Binding affinities (BindingDB)

157 measured of 192 human assays (192 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL3335630	IC50	0.47 nM
CHEMBL3335423	IC50	0.97 nM
CHEMBL3335427	IC50	1.1 nM
CHEMBL3335426	IC50	2.6 nM
CHEMBL3335425	IC50	5.8 nM
CHEMBL2178399	IC50	120 nM
(E)-N’-(4-N,N-diethylamino- 2-hydroxybenzal)-2-{N-{3- [N-(4-tert-butylbenzyl)-N- methylamino]propyl}N- methylamino}acethydrazide	EC50	130 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
(E)-N’-(2,3- dihydroxybenzal)-2-{N-{2- [N-(3- trifluoromethylbenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	170 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid	IC50	350 nM
(E)-N’-(4-N,N-diethylamino- 2-hydroxybenzal)-2-{N-{2- [N-(4-cyanobenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	530 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
(E)-N’-(2,3- dihydroxybenzal)-2-{N-{2- [N-(4-isopropylbenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	560 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
(E)-N’-(4-N,N- diethylamino-2- hydroxybenzal)-2-{N-{2- [N-(3- trifluoromethylbenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	600 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
CHEMBL2178407	IC50	740 nM
(E)-N’-(4-N,N- diethylamino-2- hydroxybenzal)-2-{N-{2- [N-(3-methoxybenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	760 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
(E)-N’-(4-N,N- diethylamino-2- hydroxybenzal)-2-{N-{2- [N-(naphthalen-1-yl- methylene)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	780 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
(E)-N’-[(3-ethoxy-2- hydroxybenzal)methylene]- 2-{N-{2-[N-(4- isopropylbenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	800 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid	IC50	800 nM
(E)-N’-(2,3- dihydroxybenzal)-2-{N-{2- [N-(3-methoxybenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	820 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
CHEMBL2178416	IC50	820 nM
(E)-N’-[(2- hydroxynaphthalen-1- yl)methylene]-2-{N-{2-[N- (naphthalen-1-yl- methylene)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	830 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinamide	IC50	900 nM
(E)-N’-[(2- hydroxynaphthalen-1- yl)methylene]-2-{N-{2-[N- (4-cyanobenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	980 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
(E)-N’-[(2- hydroxynaphthalen-1- yl)methylene]-2-{N-{2-[N- (4-isopropylbenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	1020 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
CHEMBL2178404	IC50	1070 nM
CHEMBL2178414	IC50	1180 nM
2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid methyl ester	IC50	1200 nM
CHEMBL2178403	IC50	1340 nM
CHEMBL2178419	IC50	1350 nM
2-(7-(2-chloro-4-fluorophenoxy)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid	EC50	1510 nM	US-10065928: Quinolinone compound and use thereof
2-(4-hydroxy-1-methyl-7-(naphthalen-2-yloxy)-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid	EC50	1630 nM	US-10065928: Quinolinone compound and use thereof
US20250326790, Example 37	KD	1800 nM	US-20250326790: PEPTIDES BINDING TO HYPOXIA INDUCIBLE FACTORS AND THEIR USE
CHEMBL2178417	IC50	1840 nM
CHEMBL2178405	IC50	1850 nM
(E)-N’-(3-ethoxy-2- hydroxybenzal)-2-{N-{2-[N- (4-tert-butylbenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	1860 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
2-(7-(2,3-dichlorophenoxy)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid	EC50	1970 nM	US-10065928: Quinolinone compound and use thereof
US20250326790, Example 56	KD	2100 nM	US-20250326790: PEPTIDES BINDING TO HYPOXIA INDUCIBLE FACTORS AND THEIR USE
(E)-N’-(3-ethoxy-2- hydroxybenzal)-2-{N-{2- [N-(naphthalen-1-yl- methylene)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	2110 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
CHEMBL2178410	IC50	2170 nM
CHEMBL3912024	IC50	2200 nM
2-(7-(2,5-dichlorophenoxy)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid	EC50	2250 nM	US-10065928: Quinolinone compound and use thereof
2-(7-(2,5-difluorophenoxy)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid	EC50	2260 nM	US-10065928: Quinolinone compound and use thereof
(E)-N’-(3-bromo-6- hydroxybenzal)-2-{N-{2- [N-(4-isopropylbenzyl)-N- methylamino]ethyl}N- methylamino}acethydrazide	EC50	2280 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
(E)-N’-(3-methoxy-2- hydroxybenzal)-2-{N-{2-[N- (naphthalen-1-yl-methylene)- N-methylamino]ethyl}N- methylamino)acethydrazide	EC50	2290 nM	US-10196346: Substituted acethydrazide derivative, preparation method and use thereof
CHEMBL2178415	IC50	2380 nM
CHEMBL3910426	IC50	2400 nM
2-(4-hydroxy-1-methyl-6-(naphthalen-2-yloxy)-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid	EC50	2520 nM	US-10065928: Quinolinone compound and use thereof
CHEMBL2177118	IC50	2540 nM
2-(7-(3,4-dichlorophenoxy)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid	EC50	2560 nM	US-10065928: Quinolinone compound and use thereof
3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester	IC50	2600 nM
CHEMBL2178418	IC50	2620 nM

ChEMBL bioactivities

4810 potent at pChembl≥5 of 5852 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.85	IC50	0.14	nM	MORACIN O
9.33	IC50	0.47	nM	CHEMBL3335630
9.19	IC50	0.65	nM	(+/-)-MORACIN P
9.19	IC50	0.65	nM	MORACIN P
9.01	IC50	0.97	nM	CHEMBL3335423
9.00	IC50	1	nM	CHEMBL283631
9.00	Potency	1	nM	FLUOCINONIDE
9.00	IC50	1	nM	CHEMBL1795446
8.96	IC50	1.1	nM	CHEMBL3335427
8.89	Potency	1.3	nM	AMCINONIDE
8.89	Potency	1.3	nM	CHEMBL1513684
8.89	Potency	1.3	nM	CHEMBL1355978
8.89	Potency	1.3	nM	CHEMBL1556023
8.89	Potency	1.3	nM	FLUOCINOLONE ACETONIDE
8.80	Potency	1.6	nM	CHEMBL1433436
8.80	Potency	1.6	nM	CHEMBL1473498
8.70	Potency	2	nM	CHEMBL1434739
8.70	Potency	2	nM	CHEMBL1320485
8.70	Potency	2	nM	CHEMBL1330659
8.60	Potency	2.5	nM	CHEMBL1397466
8.60	Potency	2.5	nM	CHEMBL1589998
8.60	Potency	2.5	nM	CHEMBL1356783
8.60	Potency	2.5	nM	CHEMBL1335455
8.59	IC50	2.6	nM	CHEMBL3335426
8.52	IC50	3	nM	CHEMBL2205734
8.52	IC50	3	nM	MANASSANTIN A
8.52	IC50	3	nM	CHEMBL4538400
8.52	IC50	3	nM	MANASSANTIN B
8.51	IC50	3.1	nM	CHEMBL3335421
8.49	Potency	3.2	nM	LEVOSALBUTAMOL
8.49	Potency	3.2	nM	CHEMBL1607062
8.48	IC50	3.3	nM	CHEMBL3335415
8.44	IC50	3.6	nM	ALVESPIMYCIN
8.40	Potency	4	nM	DIFLUPREDNATE
8.40	Potency	4	nM	CHEMBL1433593
8.38	IC50	4.2	nM	CHEMBL1795435
8.30	Potency	5	nM	DICHLORISONE ACETATE
8.30	Potency	5	nM	CHEMBL28140
8.30	Potency	5	nM	HYDROCORTISONE VALERATE
8.30	Potency	5	nM	FLUMETHASONE
8.30	Potency	5	nM	DESOXIMETASONE
8.24	IC50	5.8	nM	CHEMBL3335425
8.20	Potency	6.3	nM	CHEMBL1354141
8.20	Potency	6.3	nM	FLURANDRENOLIDE
8.20	Potency	6.3	nM	CHEMBL1597239
8.17	IC50	6.76	nM	MORACIN O
8.17	IC50	6.76	nM	CHEMBL1795432
8.15	IC50	7	nM	CHEMBL1795439
8.10	IC50	7.9	nM	CHEMBL3335419
8.10	IC50	7.9	nM	CHEMBL3335411

PubChem BioAssay actives

681 with measured affinity, of 3502 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
5-[6-(2-hydroxypropan-2-yl)-5,6-dihydrofuro[3,2-f][1]benzofuran-2-yl]benzene-1,3-diol	422511: Inhibition of hypoxia-induced HIF1alpha protein accumulation in human Hep3B cells treated for 30 mins measured after 12 hrs by Western blot analysis	ic50	0.0001	uM
N-[4-[2-(1-adamantyl)ethynyl]phenyl]-4-[[(2S)-4-[[6-(2-methoxyethoxymethyl)-3-pyridinyl]methyl]-2-methylpiperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0005	uM
5-(6-hydroxy-7,7-dimethyl-5,6-dihydrofuro[3,2-g]chromen-2-yl)benzene-1,3-diol	1191261: Inhibition of HIF-1alpha in human Hep3B cells cotransfected with pGL3-HRE-luciferase plasmid after 24 hrs by dual-luciferase reporter assay	ic50	0.0006	uM
5-[(6R)-6-hydroxy-7,7-dimethyl-5,6-dihydrofuro[3,2-g]chromen-2-yl]benzene-1,3-diol	422511: Inhibition of hypoxia-induced HIF1alpha protein accumulation in human Hep3B cells treated for 30 mins measured after 12 hrs by Western blot analysis	ic50	0.0006	uM
N-[4-[2-(1-adamantyl)ethynyl]phenyl]-4-[[4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0010	uM
(5S,5aS,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-5-(4-nitroanilino)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one	1597989: Inhibition of HIF-1alpha in human U373 cells	ic50	0.0010	uM
4-[(6R)-6-(2-hydroxypropan-2-yl)-5,6-dihydrofuro[3,2-f][1]benzofuran-2-yl]phenol	603554: Inhibition of hypoxia-induced HIF1alpha activation in human Hep3B cells after 16 hrs by HRE-luciferase reporter assay	ic50	0.0010	uM
N-[4-[2-(1-adamantyl)ethynyl]phenyl]-4-[[(2S)-4-[[6-(methoxymethyl)-3-pyridinyl]methyl]-2-methylpiperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0011	uM
N-[4-[2-(1-adamantyl)ethynyl]phenyl]-4-[[(2S)-2-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0026	uM
(1R,2R)-1-(1,3-benzodioxol-5-yl)-2-[4-[(2S,3R,4R,5S)-5-[4-[(1R,2R)-1-(3,4-dimethoxyphenyl)-1-hydroxypropan-2-yl]oxy-3-methoxyphenyl]-3,4-dimethyloxolan-2-yl]-2-methoxyphenoxy]propan-1-ol	401552: Inhibition of hypoxia-induced HIF1 activation in human T47D cells after 16 hrs by pTK-HRE3-luciferase reporter gene assay	ic50	0.0030	uM
6-(4-chlorophenyl)-2-[5-methyl-1-[(4-methylphenyl)methyl]pyrazol-3-yl]-1H-benzimidazole	714182: Inhibition of HIF-1alpha in human HCT116 cells under hypoxia condition by HRE-luciferase reporter gene assay	ic50	0.0030	uM
2-[(1R,2R)-1-(3,4-dimethoxyphenyl)-1-hydroxypropan-2-yl]oxy-5-[(2S,3R,4R,5S)-5-[4-[(1R,2R)-1-(3,4-dimethoxyphenyl)-1-hydroxypropan-2-yl]oxy-3-methoxyphenyl]-3,4-dimethyloxolan-2-yl]phenol	726051: Inhibition of hypoxia-induced HIF1 transcriptional activity in human T47D cells by luciferase reporter gene assay	ic50	0.0030	uM
(1R,2R)-1-(3,4-dimethoxyphenyl)-2-[4-[(1R,3S)-3-[4-[(1R,2R)-1-(3,4-dimethoxyphenyl)-1-hydroxypropan-2-yl]oxy-3-methoxyphenyl]cyclopentyl]-2-methoxyphenoxy]propan-1-ol	1546635: Activation of HIF1 in human T47D cells after 30 mins by luciferase reporter gene assay	ic50	0.0030	uM
N-[4-(2-cyclohexylethynyl)phenyl]-4-[[4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0031	uM
4-[[(2S)-2-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0033	uM
[(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-[2-(dimethylamino)ethylamino]-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate	327961: Inhibition of hypoxia-induced HIF1 activation in human AGS cells by reporter gene assay	ic50	0.0036	uM
4-[6-(2-hydroxypropan-2-yl)-5,6-dihydrofuro[3,2-f][1]benzofuran-2-yl]phenol	603554: Inhibition of hypoxia-induced HIF1alpha activation in human Hep3B cells after 16 hrs by HRE-luciferase reporter assay	ic50	0.0042	uM
N-[4-[2-(1-adamantyl)ethynyl]phenyl]-4-[[4-(2-aminopyridine-3-carbonyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0058	uM
5-[(6R)-6-(2-hydroxypropan-2-yl)-5,6-dihydrofuro[3,2-f][1]benzofuran-2-yl]benzene-1,3-diol	603554: Inhibition of hypoxia-induced HIF1alpha activation in human Hep3B cells after 16 hrs by HRE-luciferase reporter assay	ic50	0.0068	uM
2-[2-(3-methoxyphenyl)-5,6-dihydrofuro[3,2-f][1]benzofuran-6-yl]propan-2-ol	603554: Inhibition of hypoxia-induced HIF1alpha activation in human Hep3B cells after 16 hrs by HRE-luciferase reporter assay	ic50	0.0070	uM
4-[[4-(pyridin-4-ylmethyl)piperazin-1-yl]methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0079	uM
N-[4-(2-phenylethynyl)phenyl]-4-[[4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0079	uM
(14aR)-2,3,6-trimethoxy-11,12,13,14,14a,15-hexahydro-9H-phenanthro[9,10-b]quinolizine	378016: Inhibition of hypoxia-induced HIF1 activation in human AGS cells after 16 hrs by pGL3-HRE-luciferase reporter gene assay	ic50	0.0087	uM
2-[2-(3,5-dimethoxyphenyl)-5,6-dihydrofuro[3,2-f][1]benzofuran-6-yl]propan-2-ol	603554: Inhibition of hypoxia-induced HIF1alpha activation in human Hep3B cells after 16 hrs by HRE-luciferase reporter assay	ic50	0.0100	uM
2-methyl-4-[(11R)-2,8,11-trihydroxy-11-[(2R,5R)-5-[(2R,5R)-5-[(1R)-1-hydroxytridecyl]oxolan-2-yl]oxolan-2-yl]undecyl]-2H-furan-5-one	480174: Inhibition of hypoxia-induced HIF1 activation in human T47D cells in presence of 1% O2 by HRE3-TK-luc reporter assay	ic50	0.0120	uM
4-[(4-benzylpiperazin-1-yl)methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0130	uM
4-[[(2R)-2-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0130	uM
2-methyl-4-[(2R,8R,13R)-2,8,13-trihydroxy-13-[(2R,5R)-5-[(1R)-1-hydroxytridecyl]oxolan-2-yl]tridecyl]-2H-furan-5-one	480174: Inhibition of hypoxia-induced HIF1 activation in human T47D cells in presence of 1% O2 by HRE3-TK-luc reporter assay	ic50	0.0130	uM
4-[[4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0140	uM
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	726052: Inhibition of hypoxia-induced HIF1alpha transcriptional activity in human HeLa cells expressing HRE-Luc after 12 hrs by luciferase reporter gene assay	ic50	0.0140	uM
(1R,2R)-1-(3,4-dimethoxyphenyl)-2-[4-[(2S,3R,4R,5S)-5-(3,4-dimethoxyphenyl)-3,4-dimethyloxolan-2-yl]-2-methoxyphenoxy]propan-1-ol	1546636: Activation of HIF1 in human T47D cells	ic50	0.0200	uM
(3S,5S,8R,9S,10S,13R,14S,17R)-5,14-dihydroxy-13-methyl-17-(5-oxo-2H-furan-3-yl)-3-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-10-carbaldehyde	421968: Inhibition of HIF1 activation in human U251 cells stably transfected in pGL2-TK-HRE plasmid under hypoxic condition after 16 to 24 hrs by luciferase reporter gene assay	ec50	0.0200	uM
4-[[4-(2-aminopyridine-3-carbonyl)piperazin-1-yl]methyl]-N-[4-(2-phenylethynyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0210	uM
(1R,2R)-1-(3,4-dimethoxyphenyl)-2-[4-[(3S)-1-(3,4-dimethoxyphenyl)pyrrolidin-3-yl]-2-methoxyphenoxy]propan-1-ol	1546636: Activation of HIF1 in human T47D cells	ic50	0.0228	uM
N-(4-acetylphenyl)-1,2-benzoxazole-3-carboxamide	1865623: Inhibition of HIF-1alpha (unknown origin) transcriptional activity expressed in HEK293T cells co-transfected with renilla and HRE-firelfly luciferase incubated for 24 hrs by dual luciferase reporter gene assay	ic50	0.0240	uM
N-[4-(dimethylamino)phenyl]-1,2-benzoxazole-3-carboxamide	1865623: Inhibition of HIF-1alpha (unknown origin) transcriptional activity expressed in HEK293T cells co-transfected with renilla and HRE-firelfly luciferase incubated for 24 hrs by dual luciferase reporter gene assay	ic50	0.0240	uM
4-[(1R,2R)-2-[4-[(2S,3R,4R,5S)-5-[4-[(1R,2R)-1-(1,3-benzodioxol-5-yl)-1-hydroxypropan-2-yl]oxy-3-methoxyphenyl]-3,4-dimethyloxolan-2-yl]-2-methoxyphenoxy]-1-hydroxypropyl]-2-methoxyphenol	401552: Inhibition of hypoxia-induced HIF1 activation in human T47D cells after 16 hrs by pTK-HRE3-luciferase reporter gene assay	ic50	0.0300	uM
4-[[(3R)-3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0300	uM
N-[4-(2-pyridin-3-ylethynyl)phenyl]-4-[[4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0340	uM
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-methoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	726052: Inhibition of hypoxia-induced HIF1alpha transcriptional activity in human HeLa cells expressing HRE-Luc after 12 hrs by luciferase reporter gene assay	ic50	0.0340	uM
4-[[(3S)-3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]methyl]-N-[4-(trifluoromethyl)phenyl]benzamide	1188631: Inhibition of HIF1 signaling in human U251 cells expressing VEGF by VEGF promoter-driven PLAP reporter gene assay	ic50	0.0350	uM
4-[(2R)-2-[(1S,3S,5S)-3,5-dimethyl-2-oxocyclohexyl]-2-hydroxyethyl]piperidine-2,6-dione	402342: Inhibition of hypoxia-induced HIF1 activation in human HeLa cells by luciferase reporter gene assay	ic50	0.0360	uM
(1S,3R,11R,14S)-14-(hydroxymethyl)-3-[(1S,3R,11R,14S)-14-(hydroxymethyl)-18-methyl-13,17-dioxo-15,16-dithia-10,12,18-triazapentacyclo[12.2.2.01,12.03,11.04,9]octadeca-4,6,8-trien-3-yl]-18-methyl-15,16-dithia-10,12,18-triazapentacyclo[12.2.2.01,12.03,11.04,9]octadeca-4,6,8-triene-13,17-dione	714185: Inhibition of HIF-1alpha-mediated VEGF expression in human Hep3b cells by luciferase reporter gene assay	ic50	0.0400	uM
N-(4-methoxyphenyl)-1,2-benzoxazole-3-carboxamide	1865623: Inhibition of HIF-1alpha (unknown origin) transcriptional activity expressed in HEK293T cells co-transfected with renilla and HRE-firelfly luciferase incubated for 24 hrs by dual luciferase reporter gene assay	ic50	0.0400	uM
(3S,5S,8R,9S,10S,13R,14S,17R)-5,14-dihydroxy-3-[(2R,4S,5R,6R)-4-methoxy-6-methyl-5-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxyoxan-2-yl]oxy-13-methyl-17-(5-oxo-2H-furan-3-yl)-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-10-carbaldehyde	421968: Inhibition of HIF1 activation in human U251 cells stably transfected in pGL2-TK-HRE plasmid under hypoxic condition after 16 to 24 hrs by luciferase reporter gene assay	ec50	0.0400	uM
N-(4-chlorophenyl)-1,2-benzoxazole-3-carboxamide	1865623: Inhibition of HIF-1alpha (unknown origin) transcriptional activity expressed in HEK293T cells co-transfected with renilla and HRE-firelfly luciferase incubated for 24 hrs by dual luciferase reporter gene assay	ic50	0.0410	uM
N-(1,3-benzothiazol-5-yl)-1,2-benzoxazole-3-carboxamide	1865623: Inhibition of HIF-1alpha (unknown origin) transcriptional activity expressed in HEK293T cells co-transfected with renilla and HRE-firelfly luciferase incubated for 24 hrs by dual luciferase reporter gene assay	ic50	0.0420	uM
6-nitro-1-benzothiophene 1,1-dioxide	1639059: Binding affinity to Cys255 residue of C-terminal Avi/FLAG-tagged HIF-1alpha (unknown origin) after 1 hr by AlphaScreen assay	ic50	0.0430	uM
3-[6-(2-hydroxypropan-2-yl)-5,6-dihydrofuro[3,2-f][1]benzofuran-2-yl]phenol	603554: Inhibition of hypoxia-induced HIF1alpha activation in human Hep3B cells after 16 hrs by HRE-luciferase reporter assay	ic50	0.0460	uM
(14aR,15R)-2,3,6-trimethoxy-11,12,13,14,14a,15-hexahydro-9H-phenanthro[9,10-b]quinolizin-15-ol	378016: Inhibition of hypoxia-induced HIF1 activation in human AGS cells after 16 hrs by pGL3-HRE-luciferase reporter gene assay	ic50	0.0481	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Oxygen	increases activity, affects binding, affects localization, increases degradation, increases stability (+20 more)	141
cobaltous chloride	decreases ubiquitination, decreases abundance, decreases hydroxylation, increases secretion, increases response to substance (+14 more)	98
Deferoxamine	decreases reaction, affects binding, decreases abundance, increases stability, increases expression (+3 more)	28
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases expression, affects cotreatment, increases ubiquitination, affects reaction (+8 more)	25
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases expression, increases activity, decreases expression, increases reaction (+1 more)	21
sodium arsenite	decreases expression, decreases phosphorylation, decreases ubiquitination, decreases degradation, increases expression (+14 more)	19
Cycloheximide	affects expression, affects reaction, increases stability, decreases expression, decreases reaction (+5 more)	16
nickel chloride	increases expression, decreases expression, decreases hydroxylation, affects localization, increases stability (+9 more)	15
Resveratrol	increases expression, affects expression, increases reaction, increases acetylation, increases activity (+5 more)	15
Acetylcysteine	decreases reaction, increases activity, increases expression, affects cotreatment, affects localization	15
Cadmium Chloride	increases expression, affects activity, increases activity, increases cleavage, decreases reaction (+12 more)	13
Sirolimus	affects cotreatment, decreases reaction, increases expression, affects binding, increases activity (+1 more)	12
Cisplatin	decreases uptake, decreases reaction, affects activity, increases activity, affects binding (+9 more)	11
Quercetin	decreases abundance, decreases activity, increases activity, decreases degradation, increases stability (+8 more)	11
Wortmannin	affects binding, increases activity, affects cotreatment, decreases reaction, increases expression (+2 more)	10
Cobalt	decreases ubiquitination, increases abundance, increases activity, affects cotreatment, decreases degradation (+5 more)	10
nickel sulfate	increases reaction, affects reaction, affects localization, increases expression, increases stability (+7 more)	9
SB 203580	increases expression, increases stability, affects cotreatment, decreases expression, decreases reaction (+1 more)	9
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases activity, increases expression, decreases expression	9
Arsenic Trioxide	affects expression, increases expression, increases reaction, decreases expression, affects cotreatment	9
Doxorubicin	increases reaction, affects cotreatment, affects reaction, affects binding, decreases reaction (+4 more)	9
Nickel	increases reaction, decreases hydroxylation, decreases expression, affects reaction, affects localization (+8 more)	9
U 0126	decreases expression, affects cotreatment, decreases reaction, increases expression, decreases degradation (+2 more)	8
Benzo(a)pyrene	affects localization, decreases reaction, affects cotreatment, increases abundance, affects expression (+5 more)	8
chromium hexavalent ion	decreases reaction, increases stability, increases expression, affects localization, affects expression (+4 more)	7
Cadmium	affects binding, increases abundance, affects folding, increases stability, increases ubiquitination (+5 more)	7
Hydrogen Peroxide	affects reaction, decreases expression, affects localization, decreases reaction, increases expression (+3 more)	7
Rotenone	decreases reaction, increases expression, decreases degradation, increases activity, decreases expression	7
Tobacco Smoke Pollution	decreases reaction, increases expression, decreases expression, increases reaction, affects binding	7
Particulate Matter	affects cotreatment, decreases expression, increases abundance, affects reaction, increases expression (+2 more)	7

ChEMBL screening assays

427 unique, capped per target: 411 binding, 16 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1002833	Binding	Inhibition of hypoxia-induced HIF1 activation in human T47D cells carrying pTK-HER3-luc reporter gene measured by luciferase activity	Laurenditerpenol, a new diterpene from the tropical marine alga Laurenciaintricata that potently inhibits HIF-1 mediated hypoxic signaling in breast tumor cells. — J Nat Prod
CHEMBL1825601	Functional	Inhibition of HIF1alpha expression in human LN229 cells assessed as reduction of HIF-1alpha accumulation at 20 uM preincubated for 1 hr under normoxia condition followed by 24 hrs incubation under hypoxia condition by Western blotting	Sulfonamides as a new scaffold for hypoxia inducible factor pathway inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

12 cell lines: 9 cancer cell line, 2 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B1DP	Abcam HCT 116 HIF1A KO	Cancer cell line	Male
CVCL_B9JP	Abcam A-549 HIF1A KO	Cancer cell line	Male
CVCL_C3C5	A549 HIF1A -/-/-	Cancer cell line	Male
CVCL_C9DA	KSCBi005-A-10	Induced pluripotent stem cell	Male
CVCL_D7RC	Ubigene A-549 HIF1A KO	Cancer cell line	Male
CVCL_E0UC	Ubigene Hep G2 HIF1A KO	Cancer cell line	Male
CVCL_E0X5	Ubigene L-02 HIF1A KO	Cancer cell line	Female
CVCL_F1N0	HyCyte BEAS-2B KO-hHIF1A	Transformed cell line	Male
CVCL_F1V0	HyCyte WPMY-1 KO-hHIF1A	Transformed cell line	Male
CVCL_KT62	HeLa SilenciX HIF1A	Cancer cell line	Female

Clinical trials (associated diseases)

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

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