Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTQHWNA)

• DTT Name: Hypoxia-inducible factor 1 alpha (HIF-1A)
• Synonyms: bHLHe78; Transcription factor HIF-1; PASD8; PAS domain-containing protein 8; Member of PAS protein 1; MOP1; Hypoxia-inducible transcription factor (HIF)-1; Hypoxia-inducible factor 1-alpha; Hypoxia-inducible factor 1 A; Hypoxia inducible factor 1; HIF1-alpha; HIF1 alpha; HIF-1alpha; HIF-1-alpha; HIF-1 alpha; Class E basic helix-loop-helix protein 78; Basic-helix-loop-helix-PAS protein MOP1; ARNT-interacting protein; ARNT interacting protein
• Gene Name: HIF1A
• DTT Type: Clinical trial target; [1]
• UniProt ID: HIF1A_HUMAN
• TTD ID: T55610
• Sequence:
  MEGAGGANDKKKISSERRKEKSRDAARSRRSKESEVFYELAHQLPLPHNVSSHLDKASVM
  RLTISYLRVRKLLDAGDLDIEDDMKAQMNCFYLKALDGFVMVLTDDGDMIYISDNVNKYM
  GLTQFELTGHSVFDFTHPCDHEEMREMLTHRNGLVKKGKEQNTQRSFFLRMKCTLTSRGR
  TMNIKSATWKVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLVLICEPIPHPSNIEIPLDSK
  TFLSRHSLDMKFSYCDERITELMGYEPEELLGRSIYEYYHALDSDHLTKTHHDMFTKGQV
  TTGQYRMLAKRGGYVWVETQATVIYNTKNSQPQCIVCVNYVVSGIIQHDLIFSLQQTECV
  LKPVESSDMKMTQLFTKVESEDTSSLFDKLKKEPDALTLLAPAAGDTIISLDFGSNDTET
  DDQQLEEVPLYNDVMLPSPNEKLQNINLAMSPLPTAETPKPLRSSADPALNQEVALKLEP
  NPESLELSFTMPQIQDQTPSPSDGSTRQSSPEPNSPSEYCFYVDSDMVNEFKLELVEKLF
  AEDTEAKNPFSTQDTDLDLEMLAPYIPMDDDFQLRSFDQLSPLESSSASPESASPQSTVT
  VFQQTQIQEPTANATTTTATTDELKTVTKDRMEDIKILIASPSPTHIHKETTSATSSPYR
  DTQSRTASPNRAGKGVIEQTEKSHPRSPNVLSVALSQRTTVPEEELNPKILALQNAQRKR
  KMEHDGSLFQAVGIGTLLQQPDDHAATTSLSWKRVKGCKSSEQNGMEQKTIILIPSDLAC
  RLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN
• Function: 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 both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia. Functions as a master transcriptional regulator of the adaptive response to hypoxia.
• KEGG Pathway:
  HIF-1 signaling pathway (hsa04066)
  mTOR signaling pathway (hsa04150)
  Thyroid hormone signaling pathway (hsa04919)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Renal cell carcinoma (hsa05211)
  Central carbon metabolism in cancer (hsa05230)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)
  BMAL1 (R-HSA-1368108)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Circadian Clock (R-HSA-400253)
  Regulation of gene expression by Hypoxia-inducible Factor (R-HSA-1234158)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
HIF-1alpha	DM4OQRD	Lymphoma	2A80-2A86	Phase 4	[1]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IT-101	DMNDGWE	Solid tumour/cancer	2A00-2F9Z	Phase 3	[2]
2-Methoxyestradiol	DMGBPME	Pulmonary arterial hypertension	BB01.0	Phase 2	[3]
ENMD-1198	DM9BJ3G	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
EZN-2968	DM2NBC7	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]
PX-478	DM4AU8K	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pyrrolidine carboxamide derivative 1	DMJK98Z	N. A.	N. A.	Patented	[7]

References

• [1] A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther. 2008 Nov;7(11):3598-608.
• [2] CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, targets cancer stem cells and impedes resistance to antiangiogenic therapy in mouse models of breast cancer. Breast Cancer Res Treat. 2015 Apr;150(3):559-67.
• [3] 2-methoxyestradiol inhibits hypoxia-inducible factor 1alpha, tumor growth, and angiogenesis and augments paclitaxel efficacy in head and neck squam... Clin Cancer Res. 2004 Dec 15;10(24):8665-73.
• [4] ENMD-1198, a new analogue of 2-methoxyestradiol, displays both antiangiogenic and vascular-disrupting properties. Mol Cancer Ther. 2010 May;9(5):1408-18.
• [5] Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1), in patients with refractory solid tumors.Cancer Chemother Pharmacol.2014 Feb;73(2):343-8.
• [6] The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects. Mol Cancer Ther. 2009 Apr;8(4):947-58.
• [7] Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015).Expert Opin Ther Pat. 2016;26(3):309-22.