Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: HIF-prolyl hydroxylase 1 (HPH-1)
• Synonyms: Prolyl hydroxylase domain-containing protein 1; PHD1; Hypoxia-inducible factor prolyl hydroxylase 1; HPH-3; HIF-PH1; HIF-PH; Estrogen-induced tag6; Estrogen-induced tag 6; Egl nine homolog 2; EIT6; EIT-6
• Gene Name: EGLN2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Paired donor oxygen oxidoreductase
• UniProt ID: EGLN2_HUMAN
• TTD ID: T53904
• EC Number: EC 1.14.11.29
• Sequence:
  MDSPCQPQPLSQALPQLPGSSSEPLEPEPGRARMGVESYLPCPLLPSYHCPGVPSEASAG
  SGTPRATATSTTASPLRDGFGGQDGGELRPLQSEGAAALVTKGCQRLAAQGARPEAPKRK
  WAEDGGDAPSPSKRPWARQENQEAEREGGMSCSCSSGSGEASAGLMEEALPSAPERLALD
  YIVPCMRYYGICVKDSFLGAALGGRVLAEVEALKRGGRLRDGQLVSQRAIPPRSIRGDQI
  AWVEGHEPGCRSIGALMAHVDAVIRHCAGRLGSYVINGRTKAMVACYPGNGLGYVRHVDN
  PHGDGRCITCIYYLNQNWDVKVHGGLLQIFPEGRPVVANIEPLFDRLLIFWSDRRNPHEV
  KPAYATRYAITVWYFDAKERAAAKDKYQLASGQKGVQVPVSQPPTPT
• Function: Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death. Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappaB activation in hypoxic conditions. Target proteins are preferentially recognized via a LXXLAP motif. Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins.
• KEGG Pathway:
  HIF-1 signaling pathway (hsa04066)
  Pathways in cancer (hsa05200)
  Renal cell carcinoma (hsa05211)
• Reactome Pathway: Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)
• BioCyc Pathway: MetaCyc:ENSG00000171570-MON

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Daprodustat	DMRNGD2	Anaemia	3A90	Approved	[2]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
FG-4592	DM4XSQ2	Anaemia	3A90	Phase 3	[1]
BAY-85-3934	DM7NHLC	Anemia	3A00-3A9Z	Phase 2	[3]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(carboxymethylamino)-2-oxoacetic acid	DMQ2SNL	Discovery agent	N.A.	Investigative	[4]
Pyridine-2,4-dicarboxylic acid	DM4G8WX	Discovery agent	N.A.	Investigative	[4]

References

• [1] The latest advances in kidney diseases and related disorders. Drug News Perspect. 2007 Dec;20(10):647-54.
• [2] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [3] Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects. PLoS One. 2014 Nov 13;9(11):e111838.
• [4] Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone de... J Med Chem. 2010 Aug 12;53(15):5629-38.