Target Information
| Target General Information | Top | |||||
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| Target ID |
T44916
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| Target Name |
Embryonic ectoderm development protein (EED)
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| Synonyms |
hEED; WD protein associating with integrin cytoplasmic tails 1; WAIT-1
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| Gene Name |
EED
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Diffuse large B-cell lymphoma [ICD-11: 2A81] | |||||
| 2 | Prostate cancer [ICD-11: 2C82] | |||||
| Function |
Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1 and CDKN2A.
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| UniProt ID | ||||||
| Sequence |
MSEREVSTAPAGTDMPAAKKQKLSSDENSNPDLSGDENDDAVSIESGTNTERPDTPTNTP
NAPGRKSWGKGKWKSKKCKYSFKCVNSLKEDHNQPLFGVQFNWHSKEGDPLVFATVGSNR VTLYECHSQGEIRLLQSYVDADADENFYTCAWTYDSNTSHPLLAVAGSRGIIRIINPITM QCIKHYVGHGNAINELKFHPRDPNLLLSVSKDHALRLWNIQTDTLVAIFGGVEGHRDEVL SADYDLLGEKIMSCGMDHSLKLWRINSKRMMNAIKESYDYNPNKTNRPFISQKIHFPDFS TRDIHRNYVDCVRWLGDLILSKSCENAIVCWKPGKMEDDIDKIKPSESNVTILGRFDYSQ CDIWYMRFSMDFWQKMLALGNQVGKLYVWDLEVEDPHKAKCTTLTHHKCGAAIRQTSFSR DSSILIAVCDDASIWRWDRLR Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | MAK683 | Drug Info | Phase 1/2 | Diffuse large B-cell lymphoma | [1] | |
| 2 | ORIC-944 | Drug Info | Phase 1 | Prostate cancer | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | MAK683 | Drug Info | [1] | |||
| 2 | ORIC-944 | Drug Info | [3] | |||
| 3 | A-395 | Drug Info | [4] | |||
| 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: MAK683 | Ligand Info | |||||
| Structure Description | EED in complex with PRC2 allosteric inhibitor compound 22 (MAK683) | PDB:7QK4 | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | No | [5] |
| PDB Sequence |
CKYSFKCVNS
87 LKEDHNQPLF97 GVQFNWHSKE107 GDPLVFATVG117 SNRVTLYECH127 SQGEIRLLQS 137 YVDADADENF147 YTCAWTYDSN157 TSHPLLAVAG167 SRGIIRIINP177 ITMQCIKHYV 187 GHGNAINELK197 FHPRDPNLLL207 SVSKDHALRL217 WNIQTDTLVA227 IFGGVEGHRD 237 EVLSADYDLL247 GEKIMSCGMD257 HSLKLWRINS267 KRMMNAIKES277 YDYPFISQKI 294 HFPDFSTRDI304 HRNYVDCVRW314 LGDLILSKSC324 ENAIVCWKPG334 KMEDDIDKIK 344 PSESNVTILG354 RFDYSQCDIW364 YMRFSMDFWQ374 KMLALGNQVG384 KLYVWDLEVE 394 CTTLTHHKCG410 AAIRQTSFSR420 DSSILIAVCD430 DASIWRWDRL440 |
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| Ligand Name: Astemizole | Ligand Info | |||||
| Structure Description | Crystal structure of human EED | PDB:7KXT | ||||
| Method | X-ray diffraction | Resolution | 2.15 Å | Mutation | No | [6] |
| PDB Sequence |
KCKYSFKCVN
86 SLKEDHNQPL96 FGVQFNWHSK106 EGDPLVFATV116 GSNRVTLYEC126 HSQGEIRLLQ 136 SYVDADADEN146 FYTCAWTYDS156 NTSHPLLAVA166 GSRGIIRIIN176 PITMQCIKHY 186 VGHGNAINEL196 KFHPRDPNLL206 LSVSKDHALR216 LWNIQTDTLV226 AIFGGVEGHR 236 DEVLSADYDL246 LGEKIMSCGM256 DHSLKLWRIN266 SKRMMNAIKE276 SYDYNPNKTN 286 RPFISQKIHF296 PDFSTRDIHR306 NYVDCVRWLG316 DLILSKSCEN326 AIVCWKPGKM 336 EDDIDKIKPS346 ESNVTILGRF356 DYSQCDIWYM366 RFSMDFWQKM376 LALGNQVGKL 386 YVWDLEVEDP396 HKAKCTTLTH406 HKCGAAIRQT416 SFSRDSSILI426 AVCDDASIWR 436 WDRLR
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| 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).
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
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1) | 27.273 (39/143) | 9.55E-05 |
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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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| Degree | 26 | Degree centrality | 2.79E-03 | Betweenness centrality | 9.62E-05 |
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| Closeness centrality | 2.20E-01 | Radiality | 1.39E+01 | Clustering coefficient | 4.65E-01 |
| Neighborhood connectivity | 3.04E+01 | Topological coefficient | 1.09E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | ClinicalTrials.gov (NCT05413421) An Open-Label, Phase 1/1b, Study of ORIC-944 in Patients With Metastatic Prostate Cancer. U.S.National Institutes of Health. | |||||
| REF 3 | Clinical pipeline report, company report or official report of ORIC Pharmaceuticals | |||||
| REF 4 | The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat Chem Biol. 2017 Apr;13(4):389-395. | |||||
| REF 5 | Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies. J Med Chem. 2022 Apr 14;65(7):5317-5333. | |||||
| REF 6 | Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction. J Med Chem. 2021 Jun 24;64(12):8194-8207. | |||||
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