Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTADSC03)

DOT Name	Hypoxia-inducible factor 1-alpha (HIF1A)
Synonyms	HIF-1-alpha; HIF1-alpha; ARNT-interacting protein; Basic-helix-loop-helix-PAS protein MOP1; Class E basic helix-loop-helix protein 78; bHLHe78; Member of PAS protein 1; PAS domain-containing protein 8
Gene Name	HIF1A
UniProt ID	HIF1A_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1H2K; 1H2L; 1H2M; 1L3E; 1L8C; 1LM8; 1LQB; 2ILM; 3HQR; 3HQU; 4AJY; 4H6J; 5JWP; 5L9B; 5L9V; 5LA9; 5LAS; 6GFX; 6GMR; 6YW3; 7LVS; 7QGS; 8HE0; 8HE3
Pfam ID	PF11413 ; PF08778 ; PF00989 ; PF08447
Sequence	MEGAGGANDKKKISSERRKEKSRDAARSRRSKESEVFYELAHQLPLPHNVSSHLDKASVM RLTISYLRVRKLLDAGDLDIEDDMKAQMNCFYLKALDGFVMVLTDDGDMIYISDNVNKYM GLTQFELTGHSVFDFTHPCDHEEMREMLTHRNGLVKKGKEQNTQRSFFLRMKCTLTSRGR TMNIKSATWKVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLVLICEPIPHPSNIEIPLDSK TFLSRHSLDMKFSYCDERITELMGYEPEELLGRSIYEYYHALDSDHLTKTHHDMFTKGQV TTGQYRMLAKRGGYVWVETQATVIYNTKNSQPQCIVCVNYVVSGIIQHDLIFSLQQTECV LKPVESSDMKMTQLFTKVESEDTSSLFDKLKKEPDALTLLAPAAGDTIISLDFGSNDTET DDQQLEEVPLYNDVMLPSPNEKLQNINLAMSPLPTAETPKPLRSSADPALNQEVALKLEP NPESLELSFTMPQIQDQTPSPSDGSTRQSSPEPNSPSEYCFYVDSDMVNEFKLELVEKLF AEDTEAKNPFSTQDTDLDLEMLAPYIPMDDDFQLRSFDQLSPLESSSASPESASPQSTVT VFQQTQIQEPTANATTTTATTDELKTVTKDRMEDIKILIASPSPTHIHKETTSATSSPYR DTQSRTASPNRAGKGVIEQTEKSHPRSPNVLSVALSQRTTVPEEELNPKILALQNAQRKR KMEHDGSLFQAVGIGTLLQQPDDHAATTSLSWKRVKGCKSSEQNGMEQKTIILIPSDLAC RLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN
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.
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.
KEGG Pathway	HIF-1 sig.ling pathway (hsa04066 ) Mitophagy - animal (hsa04137 ) Autophagy - animal (hsa04140 ) Efferocytosis (hsa04148 ) Th17 cell differentiation (hsa04659 ) Thyroid hormone sig.ling pathway (hsa04919 ) Kaposi sarcoma-associated herpesvirus infection (hsa05167 ) Pathways in cancer (hsa05200 ) Proteoglycans in cancer (hsa05205 ) Chemical carcinogenesis - reactive oxygen species (hsa05208 ) Re.l cell carcinoma (hsa05211 ) Central carbon metabolism in cancer (hsa05230 ) Choline metabolism in cancer (hsa05231 ) PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235 )
Reactome Pathway	Cellular response to hypoxia (R-HSA-1234174 ) Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176 ) NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947 ) Circadian Clock (R-HSA-400253 ) Ub-specific processing proteases (R-HSA-5689880 ) Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807 ) PTK6 Expression (R-HSA-8849473 ) PTK6 promotes HIF1A stabilization (R-HSA-8857538 ) Neddylation (R-HSA-8951664 ) STAT3 nuclear events downstream of ALK signaling (R-HSA-9701898 ) Regulation of gene expression by Hypoxia-inducible Factor (R-HSA-1234158 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	Hypoxia-inducible factor 1-alpha (HIF1A) affects the response to substance of Gemcitabine.	[85]
Capecitabine	DMTS85L	Approved	Hypoxia-inducible factor 1-alpha (HIF1A) decreases the response to substance of Capecitabine.	[86]
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This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
AMG 386	DMQJXL4	Phase 3	Hypoxia-inducible factor 1-alpha (HIF1A) increases the secretion of AMG 386.	[87]
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3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Hypoxia-inducible factor 1-alpha (HIF1A).	[1]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Hypoxia-inducible factor 1-alpha (HIF1A).	[69]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol decreases the hydroxylation of Hypoxia-inducible factor 1-alpha (HIF1A).	[75]
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92 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[17]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[18]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[19]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[20]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[21]
Cidofovir	DMA13GD	Approved	Cidofovir affects the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[22]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[23]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[24]
Topotecan	DMP6G8T	Approved	Topotecan decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[25]
Fenofibrate	DMFKXDY	Approved	Fenofibrate affects the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[22]
Ifosfamide	DMCT3I8	Approved	Ifosfamide affects the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[22]
Clodronate	DM9Y6X7	Approved	Clodronate affects the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[22]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[26]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[27]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[19]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[28]
Acocantherin	DM7JT24	Approved	Acocantherin increases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[29]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[30]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[30]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[31]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[33]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[34]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[35]
Propofol	DMB4OLE	Approved	Propofol decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[36]
Glucosamine	DM4ZLFD	Approved	Glucosamine decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[37]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[38]
Adenosine	DMM2NSK	Approved	Adenosine increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[39]
Eicosapentaenoic acid/docosa-hexaenoic acid	DMMUCG4	Approved	Eicosapentaenoic acid/docosa-hexaenoic acid decreases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[40]
Clofibrate	DMPC1J7	Approved	Clofibrate decreases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[40]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine increases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[41]
Busulfan	DMXYJ9C	Approved	Busulfan increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[42]
Epinephrine	DM3KJBC	Approved	Epinephrine increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[43]
Gallium nitrate	DMF9O6B	Approved	Gallium nitrate decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[44]
Fludarabine	DMVRLT7	Approved	Fludarabine decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[45]
Vemurafenib	DM62UG5	Approved	Vemurafenib increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[46]
Prednisone	DM2HG4X	Approved	Prednisone increases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[41]
Digoxin	DMQCTIH	Approved	Digoxin increases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[29]
Trifluoperazine	DMKBYWI	Approved	Trifluoperazine decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[48]
Romiplostim	DM3U7SZ	Approved	Romiplostim decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[49]
Trabectedin	DMG3Y89	Approved	Trabectedin increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[50]
Idelalisib	DM602WT	Approved	Idelalisib increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[51]
Ketorolac	DMI4EL5	Approved	Ketorolac decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[19]
Triamterene	DM2HU9I	Approved	Triamterene increases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[41]
Epalrestat	DM5OGK0	Approved	Epalrestat increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[53]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[54]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[55]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[56]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[33]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[57]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[58]
Guaiacol	DMN4E7T	Phase 3	Guaiacol decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[59]
FG-4592	DM4XSQ2	Phase 3	FG-4592 increases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[60]
SNS-595	DMZE2JO	Phase 3	SNS-595 decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[61]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[42]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[62]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[63]
GDC0941	DM1YAK6	Phase 2	GDC0941 decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[64]
PF-04691502	DMS610L	Phase 2	PF-04691502 decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[65]
CR-3294	DMHJEZS	Phase 2	CR-3294 decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[66]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[67]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[68]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[70]
BETULINIC ACID	DMBUI2A	Phase 1	BETULINIC ACID decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[71]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[72]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[73]
Flavonoid derivative 1	DMCQP0B	Patented	Flavonoid derivative 1 decreases the activity of Hypoxia-inducible factor 1-alpha (HIF1A).	[74]
Phenformin	DMQ52JG	Withdrawn from market	Phenformin increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[76]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[77]
Scutellarin	DMJT1E5	Preclinical	Scutellarin decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[79]
SB 203580	DMAET6F	Terminated	SB 203580 decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[62]
Wortmannin	DM8EVK5	Terminated	Wortmannin decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[77]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[80]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[81]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[82]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[83]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Hypoxia-inducible factor 1-alpha (HIF1A).	[84]
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⏷ Show the Full List of 92 Drug(s)

5 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the degradation of Hypoxia-inducible factor 1-alpha (HIF1A).	[32]
Aluminium	DM6ECN9	Approved	Aluminium increases the localization of Hypoxia-inducible factor 1-alpha (HIF1A).	[47]
Ciclopirox	DMN5T2A	Approved	Ciclopirox increases the stability of Hypoxia-inducible factor 1-alpha (HIF1A).	[52]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the degradation of Hypoxia-inducible factor 1-alpha (HIF1A).	[78]
Deguelin	DMXT7WG	Investigative	Deguelin increases the degradation of Hypoxia-inducible factor 1-alpha (HIF1A).	[78]
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