Target Information
| Target General Information | Top | |||||
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| Target ID |
T32880
(Former ID: TTDI02433)
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| Target Name |
HIF-prolyl hydroxylase 2 (HPH-2)
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| 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
Click to Show/Hide
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| Gene Name |
EGLN1
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| Target Type |
Patented-recorded target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Acute disease anaemia [ICD-11: 3A90] | |||||
| 2 | Urinary system disease [ICD-11: GC2Z] | |||||
| 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.
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| BioChemical Class |
Paired donor oxygen oxidoreductase
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| UniProt ID | ||||||
| EC Number |
EC 1.14.11.29
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| Sequence |
MANDSGGPGGPSPSERDRQYCELCGKMENLLRCSRCRSSFYCCKEHQRQDWKKHKLVCQG
SEGALGHGVGPHQHSGPAPPAAVPPPRAGAREPRKAAARRDNASGDAAKGKVKAKPPADP AAAASPCRAAAGGQGSAVAAEAEPGKEEPPARSSLFQEKANLYPPSNTPGDALSPGGGLR PNGQTKPLPALKLALEYIVPCMNKHGICVVDDFLGKETGQQIGDEVRALHDTGKFTDGQL VSQKSDSSKDIRGDKITWIEGKEPGCETIGLLMSSMDDLIRHCNGKLGSYKINGRTKAMV ACYPGNGTGYVRHVDNPNGDGRCVTCIYYLNKDWDAKVSGGILRIFPEGKAQFADIEPKF DRLLFFWSDRRNPHEVQPAYATRYAITVWYFDADERARAKVKYLTGEKGVRVELNKPSDS VGKDVF Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T91N2D | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | FG-4592 | Drug Info | Phase 3 | Kidney disease | [2], [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 36 Inhibitor drugs | + | ||||
| 1 | FG-4592 | Drug Info | [4] | |||
| 2 | US10100051, Compound 1 | Drug Info | [5] | |||
| 3 | US10100051, Compound 10 | Drug Info | [5] | |||
| 4 | US10100051, Compound 11 | Drug Info | [5] | |||
| 5 | US10100051, Compound 2 | Drug Info | [5] | |||
| 6 | US10149841, Compound 1 | Drug Info | [6] | |||
| 7 | US10149841, Compound 19 | Drug Info | [6] | |||
| 8 | US10149841, Compound 5 | Drug Info | [6] | |||
| 9 | US10149841, Compound 9 | Drug Info | [6] | |||
| 10 | US8536181, A41 | Drug Info | [7] | |||
| 11 | US8536181, C14 | Drug Info | [7] | |||
| 12 | US8536181, C17 | Drug Info | [8] | |||
| 13 | US8536181, C35 | Drug Info | [7] | |||
| 14 | US8598210, Table XV, 1 | Drug Info | [9] | |||
| 15 | US8598210, Table XV, 2 | Drug Info | [10] | |||
| 16 | US8598210, Table XV, 4 | Drug Info | [9] | |||
| 17 | US8598210, Table XV, 5 | Drug Info | [11] | |||
| 18 | US8921389, 1 | Drug Info | [12] | |||
| 19 | US8921389, 123 | Drug Info | [13] | |||
| 20 | US8921389, 2 | Drug Info | [12] | |||
| 21 | US8921389, 210 | Drug Info | [12] | |||
| 22 | US8921389, 22 | Drug Info | [13] | |||
| 23 | US9340511, 2 | Drug Info | [14] | |||
| 24 | US9340511, 5 | Drug Info | [14] | |||
| 25 | US9340511, 6 | Drug Info | [15] | |||
| 26 | US9340511, 7 | Drug Info | [14] | |||
| 27 | US9409892, 136 | Drug Info | [16] | |||
| 28 | US9409892, 148 | Drug Info | [16] | |||
| 29 | US9409892, 19 | Drug Info | [16] | |||
| 30 | US9409892, 59 | Drug Info | [16] | |||
| 31 | US9422240, 1-282 | Drug Info | [17] | |||
| 32 | US9422240, 1-286 | Drug Info | [17] | |||
| 33 | US9422240, 1-297 | Drug Info | [17] | |||
| 34 | US9422240, 1-298 | Drug Info | [17] | |||
| 35 | IOX1 | Drug Info | [18] | |||
| 36 | IOX2 | Drug Info | [19] | |||
| Activator | [+] 1 Activator drugs | + | ||||
| 1 | KRH-102053 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: BAY 853934 | Ligand Info | |||||
| Structure Description | HIF Prolyl Hydroxylase 2 (PHD2/EGLN1) in Complex with 1-(6-morpholinopyrimidin-4-yl)-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-ol (Molidustat) | PDB:6ZBO | ||||
| Method | X-ray diffraction | Resolution | 1.79 Å | Mutation | No | [20] |
| PDB Sequence |
LPALKLALEY
197 IVPCMNKHGI207 CVVDDFLGKE217 TGQQIGDEVR227 ALHDTGKFTG253 DKITWIEGKE 263 PGCETIGLLM273 SSMDDLIRHC283 NGKLGSYKIN293 GRTKAMVACY303 PGNGTGYVRH 313 VDNPNGDGRC323 VTCIYYLNKD333 WDAKVSGGIL343 RIFPEGKAQF353 ADIEPKFDRL 363 LFFWSDRRNP373 HEVQPAYATR383 YAITVWYFDA393 DERARAKVKY403 LTGE |
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| Ligand Name: AKB-6548 | Ligand Info | |||||
| Structure Description | CRYSTAL STRUCTURE OF PHD2 CATALYTIC DOMAIN (CID 7465) IN COMPLEX WITH AKB-6548 AT 1.8 A RESOLUTION | PDB:7UMP | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [21] |
| PDB Sequence |
LPALKLALEY
197 IVPCMNKHGI207 CVVDDFLGKE217 TGQQIGDEVR227 ALHDTGKFTD237 GMLVAQKSDS 247 SKDIRGDKIT257 WIEGKEPGCE267 TIGLLMSSMD277 DLIRHCNGKL287 GSYKINGRTK 297 AMVACYPGNG307 TGYVRHVDNP317 NGDGRCVTCI327 YYLNKDWDAK337 VSGGILRIFP 347 EGKAQFADIE357 PKFDRLLFFW367 SDRRNPHEVQ377 PAYATRYAIT387 VWYFDADERA 397 RAKVKY
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| HIF-1 signaling pathway | hsa04066 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 1.33E-04 |
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| Closeness centrality | 2.31E-01 | Radiality | 1.41E+01 | Clustering coefficient | 1.79E-01 |
| Neighborhood connectivity | 3.23E+01 | Topological coefficient | 1.52E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | HIF-1 signaling pathway | |||||
| 2 | Pathways in cancer | |||||
| 3 | Renal cell carcinoma | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Hypoxia response via HIF activation | |||||
| PID Pathway | [+] 3 PID Pathways | + | ||||
| 1 | HIF-2-alpha transcription factor network | |||||
| 2 | Hypoxic and oxygen homeostasis regulation of HIF-1-alpha | |||||
| 3 | HIF-1-alpha transcription factor network | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha | |||||
| References | Top | |||||
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| REF 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). | |||||
| REF 2 | 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. (Ligand id: 8454). | |||||
| REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800023523) | |||||
| REF 4 | Crystalline forms of a prolyl hydroxylase inhibitor. US9115085. | |||||
| REF 5 | Compound of 5-hydroxyl-1,7-naphthyridine substituted by aryloxy or heteroaryloxy, preparation method thereof and pharmaceutical use thereof. US10100051. | |||||
| REF 6 | Compound of 3-hydroxyl pyridine, preparation method thereof and pharmaceutical use thereof. US10149841. | |||||
| REF 7 | Prolyl hydroxylase inhibitors. US8536181. | |||||
| REF 8 | Methods for increasing the stabilization of hypoxia inducible factor-1 alpha. US8778412. | |||||
| REF 9 | Prolyl hydroxylase inhibitors and methods of use. US8598210. | |||||
| REF 10 | Prolyl hydroxylase inhibitors and methods of use. US9598370. | |||||
| REF 11 | Prolyl hydroxylase inhibitors and method of use. US8722895. | |||||
| REF 12 | Naphthyridine derivatives as inhibitors of Hypoxia inducible factor (HIF) hydroxylase. US9695170. | |||||
| REF 13 | Naphthyridine derivatives as inhibitors of hypoxia inducible factor (HIF) hydroxylase. US8921389. | |||||
| REF 14 | Process for making isoquinoline compounds. US9708269. | |||||
| REF 15 | Process for making isoquinoline compounds. US9340511. | |||||
| REF 16 | 4-hydroxy-isoquinoline compounds as HIF hydroxylase inhibitors. US9409892. | |||||
| REF 17 | Partially saturated nitrogen-containing heterocyclic compound. US9422240. | |||||
| REF 18 | A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1. ChemMedChem. 2014 Mar;9(3):566-71. | |||||
| REF 19 | Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases. ACS Chem Biol. 2013 Jul 19;8(7):1488-96. | |||||
| REF 20 | Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat. ChemMedChem. 2021 Jul 6;16(13):2082-2088. | |||||
| REF 21 | Preclinical Characterization of Vadadustat (AKB-6548), an Oral Small Molecule Hypoxia-Inducible Factor Prolyl-4-Hydroxylase Inhibitor, for the Potential Treatment of Renal Anemia. J Pharmacol Exp Ther. 2022 Oct;383(1):11-24. | |||||
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