Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9ISBX)

• DTT Name: HIF-prolyl hydroxylase 2 (HPH-2)
• Synonyms: SM-20; Prolyl hydroxylase domain-containing protein 2; PHD2; Hypoxia-inducible factor prolyl hydroxylase 2; HPH-2; HIF-PH2; Egl nine homolog 1; C1orf12
• Gene Name: EGLN1
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Paired donor oxygen oxidoreductase
• UniProt ID: EGLN1_HUMAN
• TTD ID: T32880
• EC Number: EC 1.14.11.29
• Sequence:
  MANDSGGPGGPSPSERDRQYCELCGKMENLLRCSRCRSSFYCCKEHQRQDWKKHKLVCQG
  SEGALGHGVGPHQHSGPAPPAAVPPPRAGAREPRKAAARRDNASGDAAKGKVKAKPPADP
  AAAASPCRAAAGGQGSAVAAEAEPGKEEPPARSSLFQEKANLYPPSNTPGDALSPGGGLR
  PNGQTKPLPALKLALEYIVPCMNKHGICVVDDFLGKETGQQIGDEVRALHDTGKFTDGQL
  VSQKSDSSKDIRGDKITWIEGKEPGCETIGLLMSSMDDLIRHCNGKLGSYKINGRTKAMV
  ACYPGNGTGYVRHVDNPNGDGRCVTCIYYLNKDWDAKVSGGILRIFPEGKAQFADIEPKF
  DRLLFFWSDRRNPHEVQPAYATRYAITVWYFDADERARAKVKYLTGEKGVRVELNKPSDS
  VGKDVF
• Function: Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. 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. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif.
• 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)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
FG-4592	DM4XSQ2	Anaemia	3A90	Phase 3	[2]

33 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
US10100051, Compound 1	DMJKS4X	N. A.	N. A.	Patented	[3]
US10100051, Compound 10	DMQ7ODW	N. A.	N. A.	Patented	[3]
US10100051, Compound 11	DM2DEOA	N. A.	N. A.	Patented	[3]
US10100051, Compound 2	DMWESZ1	N. A.	N. A.	Patented	[3]
US10149841, Compound 1	DMEVGR6	N. A.	N. A.	Patented	[4]
US10149841, Compound 19	DMYSI9J	N. A.	N. A.	Patented	[4]
US10149841, Compound 5	DMBS50K	N. A.	N. A.	Patented	[4]
US10149841, Compound 9	DMS415A	N. A.	N. A.	Patented	[4]
US8536181, A41	DMF9LNO	N. A.	N. A.	Patented	[5]
US8536181, C14	DMZNF59	N. A.	N. A.	Patented	[5]
US8536181, C17	DMRTL63	N. A.	N. A.	Patented	[6]
US8536181, C35	DMAM51Z	N. A.	N. A.	Patented	[5]
US8598210, Table XV, 1	DM9YI3K	N. A.	N. A.	Patented	[7]
US8598210, Table XV, 2	DMDK98P	N. A.	N. A.	Patented	[8]
US8598210, Table XV, 4	DM3XWMO	N. A.	N. A.	Patented	[7]
US8598210, Table XV, 5	DMEU5ST	N. A.	N. A.	Patented	[9]
US8921389, 1	DM34KXF	N. A.	N. A.	Patented	[10]
US8921389, 123	DM8NE12	N. A.	N. A.	Patented	[11]
US8921389, 2	DMX7KDR	N. A.	N. A.	Patented	[10]
US8921389, 210	DME1A80	N. A.	N. A.	Patented	[10]
US8921389, 22	DMIY68N	N. A.	N. A.	Patented	[11]
US9340511, 2	DM0GOCZ	N. A.	N. A.	Patented	[12]
US9340511, 5	DMFQERG	N. A.	N. A.	Patented	[12]
US9340511, 6	DMRL0WA	N. A.	N. A.	Patented	[13]
US9340511, 7	DMC0PUI	N. A.	N. A.	Patented	[12]
US9409892, 136	DMMFC0V	N. A.	N. A.	Patented	[14]
US9409892, 148	DMZJTSP	N. A.	N. A.	Patented	[14]
US9409892, 19	DMHF2OX	N. A.	N. A.	Patented	[14]
US9409892, 59	DMWAL5Q	N. A.	N. A.	Patented	[14]
US9422240, 1-282	DMV4AHL	N. A.	N. A.	Patented	[15]
US9422240, 1-286	DM0S2UK	N. A.	N. A.	Patented	[15]
US9422240, 1-297	DMST6IF	N. A.	N. A.	Patented	[15]
US9422240, 1-298	DMH7DL5	N. A.	N. A.	Patented	[15]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IOX1	DMYG0M5	Discovery agent	N.A.	Investigative	[16]
IOX2	DMQ0X7I	Discovery agent	N.A.	Investigative	[17]
KRH-102053	DMXFBER	Solid tumour/cancer	2A00-2F9Z	Investigative	[1]

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: HIF-prolyl hydroxylase 2 (EGLN1) DME Info
• Gene Name: EGLN1

1 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Vitamin C	DMXJ7O8	Adenocarcinoma	2D40	Approved	[18]

1 Investigative Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
alpha-ketoglutaric acid	DM5LFYN	Discovery agent	N.A.	Investigative	[18]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2833).
• [2] Crystalline forms of a prolyl hydroxylase inhibitor. US9115085.
• [3] Compound of 5-hydroxyl-1,7-naphthyridine substituted by aryloxy or heteroaryloxy, preparation method thereof and pharmaceutical use thereof. US10100051.
• [4] Compound of 3-hydroxyl pyridine, preparation method thereof and pharmaceutical use thereof. US10149841.
• [5] Prolyl hydroxylase inhibitors. US8536181.
• [6] Methods for increasing the stabilization of hypoxia inducible factor-1 alpha. US8778412.
• [7] Prolyl hydroxylase inhibitors and methods of use. US8598210.
• [8] Prolyl hydroxylase inhibitors and methods of use. US9598370.
• [9] Prolyl hydroxylase inhibitors and method of use. US8722895.
• [10] Naphthyridine derivatives as inhibitors of Hypoxia inducible factor (HIF) hydroxylase. US9695170.
• [11] Naphthyridine derivatives as inhibitors of hypoxia inducible factor (HIF) hydroxylase. US8921389.
• [12] Process for making isoquinoline compounds. US9708269.
• [13] Process for making isoquinoline compounds. US9340511.
• [14] 4-hydroxy-isoquinoline compounds as HIF hydroxylase inhibitors. US9409892.
• [15] Partially saturated nitrogen-containing heterocyclic compound. US9422240.
• [16] A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1. ChemMedChem. 2014 Mar;9(3):566-71.
• [17] Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases. ACS Chem Biol. 2013 Jul 19;8(7):1488-96.
• [18] Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem. 2003 Aug 15;278(33):30772-80.