Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTHGL48)

• DTT Name: AP endonuclease 1 (APEX1)
• 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
• Gene Name: APEX1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Alpha-carbonic anhydrase
• UniProt ID: APEX1_HUMAN
• TTD ID: T13348
• EC Number: EC 3.1.-.-
• Sequence:
  MPKRGKKGAVAEDGDELRTEPEAKKSKTAAKKNDKEAAGEGPALYEDPPDQKTSPSGKPA
  TLKICSWNVDGLRAWIKKKGLDWVKEEAPDILCLQETKCSENKLPAELQELPGLSHQYWS
  APSDKEGYSGVGLLSRQCPLKVSYGIGDEEHDQEGRVIVAEFDSFVLVTAYVPNAGRGLV
  RLEYRQRWDEAFRKFLKGLASRKPLVLCGDLNVAHEEIDLRNPKGNKKNAGFTPQERQGF
  GELLQAVPLADSFRHLYPNTPYAYTFWTYMMNARSKNVGWRLDYFLLSHSLLPALCDSKI
  RSKALGSDHCPITLYLAL
• 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.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway:
  POLB-Dependent Long Patch Base Excision Repair (R-HSA-110362)
  Resolution of AP sites via the multiple-nucleotide patch replacement pathway (R-HSA-110373)
  PCNA-Dependent Long Patch Base Excision Repair (R-HSA-5651801)
  Abasic sugar-phosphate removal via the single-nucleotide replacement pathway (R-HSA-73930)
  Resolution of Abasic Sites (AP sites) (R-HSA-73933)
  Displacement of DNA glycosylase by APEX1 (R-HSA-110357)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
APX3330	DMU6NBO	Diabetic retinopathy	9B71.0	Phase 2	[2]
APX-3330	DMXIMQT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[1]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,3-bis(1,3-benzothiazol-2-ylthio)acetone	DMP86R3	Glioma	2A00.0	Investigative	[3]
3-benzofuran-2-yl-2-benzothiazol-2-yl-3-oxo-propanenitrile	DMWLIK1	Glioma	2A00.0	Investigative	[3]
5-fluoro-1H-indole-2-carboxylic acid	DM9U1HV	Glioma	2A00.0	Investigative	[3]

References

• [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.
• [2] Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. NPJ Precis Oncol. 2017;1:19.
• [3] Development and evaluation of human AP endonuclease inhibitors in melanoma and glioma cell lines. Br J Cancer. 2011 Feb 15;104(4):653-63.