Target Information
Target General Information | Top | |||||
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Target ID |
T13348
(Former ID: TTDR00967)
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Target Name |
AP endonuclease 1 (APEX1)
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Synonyms |
Redox factor-1; REF1; REF-1; HAP1; DNA-(apurinic or apyrimidinic site) lyase; Apurinic-apyrimidinic endonuclease 1; APX; APEX nuclease; APEX; APEN; APE1; APE-1; APE
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Gene Name |
APEX1
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Retinopathy [ICD-11: 9B71] | |||||
2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 are DNA repair and redox regulation of transcriptional factors. Functions as a apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents. Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. Does also incise at AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of R-loop structures, and single-stranded RNA molecules. Has a 3'-5' exoribonuclease activity on mismatched deoxyribonucleotides at the 3' termini of nicked or gapped DNA molecules during short-patch BER. Possesses a DNA 3' phosphodiesterase activity capable of removing lesions (such as phosphoglycolate) blocking the 3' side of DNA strand breaks. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. Acts as a loading factor for POLB onto non-incised AP sites in DNA and stimulates the 5'-terminal deoxyribose 5'-phosphate (dRp) excision activity of POLB. Plays a role in the protection from granzymes-mediated cellular repair leading to cell death. Also involved in the DNA cleavage step of class switch recombination (CSR). On the other hand, APEX1 also exerts reversible nuclear redox activity to regulate DNA binding affinity and transcriptional activity of transcriptional factors by controlling the redox status of their DNA-binding domain, such as the FOS/JUN AP-1 complex after exposure to IR. Involved in calcium-dependent down-regulation of parathyroid hormone (PTH) expression by binding to negative calcium response elements (nCaREs). Together with HNRNPL or the dimer XRCC5/XRCC6, associates with nCaRE, acting as an activator of transcriptional repression. Stimulates the YBX1-mediated MDR1 promoter activity, when acetylated at Lys-6 and Lys-7, leading to drug resistance. Acts also as an endoribonuclease involved in the control of single-stranded RNA metabolism. Plays a role in regulating MYC mRNA turnover by preferentially cleaving in between UA and CA dinucleotides of the MYC coding region determinant (CRD). In association with NMD1, plays a role in the rRNA quality control process during cell cycle progression. Associates, together with YBX1, on the MDR1 promoter. Together with NPM1, associates with rRNA. Binds DNA and RNA.
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BioChemical Class |
Alpha-carbonic anhydrase
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UniProt ID | ||||||
EC Number |
EC 3.1.-.-
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Sequence |
MPKRGKKGAVAEDGDELRTEPEAKKSKTAAKKNDKEAAGEGPALYEDPPDQKTSPSGKPA
TLKICSWNVDGLRAWIKKKGLDWVKEEAPDILCLQETKCSENKLPAELQELPGLSHQYWS APSDKEGYSGVGLLSRQCPLKVSYGIGDEEHDQEGRVIVAEFDSFVLVTAYVPNAGRGLV RLEYRQRWDEAFRKFLKGLASRKPLVLCGDLNVAHEEIDLRNPKGNKKNAGFTPQERQGF GELLQAVPLADSFRHLYPNTPYAYTFWTYMMNARSKNVGWRLDYFLLSHSLLPALCDSKI RSKALGSDHCPITLYLAL Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T39M81 |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | APX3330 | Drug Info | Phase 2 | Diabetic retinopathy | [2] | |
2 | APX-3330 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 5 Inhibitor drugs | + | ||||
1 | APX3330 | Drug Info | [4] | |||
2 | APX-3330 | Drug Info | [1] | |||
3 | 1,3-bis(1,3-benzothiazol-2-ylthio)acetone | Drug Info | [5] | |||
4 | 3-benzofuran-2-yl-2-benzothiazol-2-yl-3-oxo-propanenitrile | Drug Info | [5] | |||
5 | 5-fluoro-1H-indole-2-carboxylic acid | Drug Info | [5] |
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: 2-Phosphoglycolic Acid | Ligand Info | |||||
Structure Description | APE1 exonuclease substrate complex with phosphoglycolate | PDB:5WN2 | ||||
Method | X-ray diffraction | Resolution | 2.29 Å | Mutation | Yes | [6] |
PDB Sequence |
ALYEDPPDQK
52 TSPSGKPATL62 KICSWNVDGL72 RAWIKKKGLD82 WVKEEAPDIL92 CLQQTKCSEN 102 KLPAELQELP112 GLSHQYWSAP122 SDKEGYSGVG132 LLSRQAPLKV142 SYGIGDEEHD 152 QEGRVIVAEF162 DSFVLVTAYV172 PNAGRGLVRL182 EYRQRWDEAF192 RKFLKGLASR 202 KPLVLCGNLN212 VAHEEIDLRN222 PKGNKKNAGF232 TPQERQGFGE242 LLQAVPLADS 252 FRHLYPNTPY262 AYTFWTYMMN272 ARSKNVGWRL282 DYFLLSHSLL292 PALCDSKIRS 302 KALGSDHCPI312 TLYLAL
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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).
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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Base excision repair | hsa03410 | Affiliated Target |
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Class: Genetic Information Processing => Replication and repair | Pathway Hierarchy |
Degree | 20 | Degree centrality | 2.15E-03 | Betweenness centrality | 3.01E-03 |
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Closeness centrality | 2.45E-01 | Radiality | 1.43E+01 | Clustering coefficient | 1.21E-01 |
Neighborhood connectivity | 3.47E+01 | Topological coefficient | 6.55E-02 | 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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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 |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
1 | Base excision repair | |||||
PID Pathway | [+] 1 PID Pathways | + | ||||
1 | HIF-2-alpha transcription factor network | |||||
WikiPathways | [+] 3 WikiPathways | + | ||||
1 | Spinal Cord Injury | |||||
2 | TSH signaling pathway | |||||
3 | Base Excision Repair |
References | Top | |||||
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REF 1 | Inhibition of APE1/Ref-1 redox activity with APX3330 blocks retinal angiogenesis in vitro and in vivo. Vision Res. 2011 Jan;51(1):93-100. | |||||
REF 2 | ClinicalTrials.gov (NCT04692688) Study of the Safety and Efficacy of APX3330 in Diabetic Retinopathy (ZETA-1). U.S. National Institutes of Health. | |||||
REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 4 | Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. NPJ Precis Oncol. 2017;1:19. | |||||
REF 5 | Development and evaluation of human AP endonuclease inhibitors in melanoma and glioma cell lines. Br J Cancer. 2011 Feb 15;104(4):653-63. | |||||
REF 6 | Molecular snapshots of APE1 proofreading mismatches and removing DNA damage. Nat Commun. 2018 Jan 26;9(1):399. |
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