APEX1

Summary

APEX1 (apurinic/apyrimidinic endodeoxyribonuclease 1, HGNC:587) is a protein-coding gene on chromosome 14q11.2, encoding DNA repair nuclease/redox regulator APEX1 (P27695). Multifunctional protein that plays a central role in the cellular response to oxidative stress.

The APEX gene encodes the major AP endonuclease in human cells. It encodes the APEX endonuclease, a DNA repair enzyme with apurinic/apyrimidinic (AP) activity. Such AP activity sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. The AP sites are the most frequent pre-mutagenic lesions that can prevent normal DNA replication. Splice variants have been found for this gene; all encode the same protein. Disruptions in the biological functions related to APEX are associated with many various malignancies and neurodegenerative diseases.

Source: NCBI Gene 328 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis (Limited, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 194 total
• Druggable target: yes — 53 molecules with ChEMBL bioactivity
• Transcription factor: yes — 45 downstream targets (CollecTRI)
• MANE Select transcript: NM_001641

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:587
Approved symbol	APEX1
Name	apurinic/apyrimidinic endodeoxyribonuclease 1
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	APE, REF1, HAP1, APX, APEN, REF-1, APE-1, APE1
Ensembl gene	ENSG00000100823
Ensembl biotype	protein_coding
OMIM	107748
Entrez	328

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 29 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000216714, ENST00000398030, ENST00000438886, ENST00000553368, ENST00000553555, ENST00000553681, ENST00000554325, ENST00000554813, ENST00000555306, ENST00000555414, ENST00000555839, ENST00000556054, ENST00000556296, ENST00000557054, ENST00000557150, ENST00000557159, ENST00000557181, ENST00000557344, ENST00000557365, ENST00000557592, ENST00000899615, ENST00000899616, ENST00000899617, ENST00000899618, ENST00000899619, ENST00000899620, ENST00000936687, ENST00000936688, ENST00000936689, ENST00000936690, ENST00000936691, ENST00000936692, ENST00000936693, ENST00000936694, ENST00000936695, ENST00000956430

RefSeq mRNA: 4 — MANE Select: NM_001641 NM_001244249, NM_001641, NM_080648, NM_080649

CCDS: CCDS9550

Canonical transcript exons

ENST00000216714 — 5 exons

Exon	Start	End
ENSE00000889014	20455578	20455703
ENSE00002441263	20456991	20457767
ENSE00002488138	20455226	20455394
ENSE00003540899	20455914	20456101
ENSE00003788427	20456668	20456860

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 183.2026 / max 2300.0426, expressed in 1824 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138428	155.5796	1823
138429	17.6717	1804
138427	8.1032	1718
138430	0.9957	631
138432	0.4919	243
138431	0.3603	112

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	99.23	gold quality
embryo	UBERON:0000922	99.17	gold quality
ventricular zone	UBERON:0003053	98.76	gold quality
cortical plate	UBERON:0005343	98.75	gold quality
islet of Langerhans	UBERON:0000006	97.93	gold quality
right adrenal gland	UBERON:0001233	97.90	gold quality
right adrenal gland cortex	UBERON:0035827	97.79	gold quality
left ovary	UBERON:0002119	97.78	gold quality
right ovary	UBERON:0002118	97.77	gold quality
left adrenal gland cortex	UBERON:0035825	97.75	gold quality
gall bladder	UBERON:0002110	97.74	gold quality
rectum	UBERON:0001052	97.72	gold quality
stromal cell of endometrium	CL:0002255	97.71	gold quality
left adrenal gland	UBERON:0001234	97.68	gold quality
adrenal cortex	UBERON:0001235	97.59	gold quality
endometrium epithelium	UBERON:0004811	97.54	gold quality
parietal pleura	UBERON:0002400	97.53	gold quality
ovary	UBERON:0000992	97.41	gold quality
vermiform appendix	UBERON:0001154	97.40	gold quality
body of stomach	UBERON:0001161	97.40	gold quality
lymph node	UBERON:0000029	97.39	gold quality
skin of abdomen	UBERON:0001416	97.38	gold quality
monocyte	CL:0000576	97.37	gold quality
mononuclear cell	CL:0000842	97.30	gold quality
adrenal gland	UBERON:0002369	97.30	gold quality
leukocyte	CL:0000738	97.28	gold quality
skin of leg	UBERON:0001511	97.28	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.27	gold quality
body of pancreas	UBERON:0001150	97.23	gold quality
metanephros cortex	UBERON:0010533	97.22	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	64.62
E-HCAD-10	yes	36.50
E-CURD-112	yes	22.47
E-MTAB-10042	yes	13.30
E-HCAD-1	yes	11.58
E-GEOD-125970	yes	10.76
E-CURD-114	yes	7.30
E-MTAB-9801	yes	6.28
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

45 targets.

Target	Regulation
ABCB1
ACTB
AP1
APEX1
APOD
BLK	Activation
BRCA1
CA2
CAT
CCL2	Activation
CD19	Activation
CDKN1A
CXCL8
CYP11B2	Repression
GAL
GDNF
GFRA1
GHRHR
HAP1
HHEX
HIRA
IL6
LIG1
LIG3
MGMT
MNT
MPG
NFKB1	Activation
NQO1
OGG1

Upstream regulators (CollecTRI, top): AP1, APEX1, ATF2, CREB1, EGR1, GATA2, HIF1A, MITF, MYC, MYCN, NFKB, SP1, STAT3, TCF12, TP53, USF1

miRNA regulators (miRDB)

25 targeting APEX1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-4752	98.71	68.04	833
HSA-MIR-376B-5P	98.46	66.40	606
HSA-MIR-376C-5P	98.46	66.64	589
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-3921	97.81	67.45	1431
HSA-MIR-4653-5P	97.22	67.72	1429
HSA-MIR-27A-5P	97.01	65.63	528
HSA-MIR-4790-3P	96.63	67.08	806
HSA-MIR-4680-5P	96.43	67.15	893
HSA-MIR-635	96.00	65.54	687
HSA-MIR-6774-5P	95.94	65.18	722
HSA-MIR-6805-5P	95.79	64.86	670
HSA-MIR-7975	95.04	66.76	516

Literature-anchored findings (GeneRIF, showing 40)

• Physical interaction of APE1 with flap endonuclease 1 (FEN1) by addition of APE1 to the excision reaction mixture slightly stimulates the removal of the displaced flap by FEN1, thus coordinating long-patch base excision repair. (PMID:11601988)
• In the 58 cases analyzed, mean Ap endo activity was 7.3-fold higher in gliomas than in adjacent histologically normal brain. (PMID:11705870)
• AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like repressor element in the AP-endonuclease 1 promoter (PMID:11809897)
• high levels of nuclear expression in pediatric embryonal rhabdomyosarcoma and low levels in alveolar rhabdomyosarcoma (ARMS; since APE activates daunomycin, ARMS is daunomycin-resistant but embryonal rhabdomyosarcoma is not. (PMID:11846302)
• Determinants in nuclease specificity of Ape1 and Ape2, human homologues of Escherichia coli exonuclease III (PMID:11866537)
• redox factor-1 in the regulation of endothelial oxidative stress and apoptosis (PMID:12058277)
• altered posttranslational modification of Ref-1 is involved in uterine smooth muscle tumorigenesis. (PMID:12161506)
• stimulates both FEN1 and DNA ligase I for progression through the base excision repair pathway (PMID:12200445)
• APE/REF1 is increased &competent in the brain & spinal cord of individuals with amyotrophic lateral sclerosis. It is upredulated in spinal cord astrocytes& white matter pathways in familial ALS. (PMID:12230304)
• The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress. (PMID:12231548)
• These results demonstrated that oxidoreductive modification of Cys-45 and Cys-57 via Ref-1 plays a role in redox regulation of Pax-8 in living cells. (PMID:12237116)
• findings suggest a two-stage model of APE/Ref-1 behaviour during malignant thyrocyte transformation: 1) simple hyperplasia and upregulation of APE/Ref-1 in the nucleus and 2)nuclear levels drop as the cell becomes progressively undifferentiated (PMID:12242029)
• H(2)O(2) induces translocation of APE/REF-1 to mitochondria in the Raji B-cell line. (PMID:12384995)
• The 3(’)–>5(’)-exonucleolytic activity of human apurinic/apyrimidinic endonuclease 1 (APE1) on mispaired DNA at the 3(’)-termini of recessed, nicked or gapped DNA molecules was analyzed. (PMID:12480540)
• substrate selectivity of mammalian NTH1 and the concomitant selective stimulation of activity by APE1 are indicative of selective repair of oxidative damage in different regions of the genome (PMID:12519758)
• The amino terminal portion of HSP70 stimulates the activity of HAP1. (PMID:12547389)
• Repression of renin expression by intracellular calcium may be mediated by the calcium-induced translocation of Ref-1 to the nucleus, where it binds to the renin promoter nCaRE, to repress the transcription of the renin gene. (PMID:12569263)
• APE1 may exist in two different conformations, and each conformation has a preference for a substrate (PMID:12624104)
• AN34 and Ape1 participate in the process of chromatin fragmentation during apoptosis. (PMID:12842873)
• Ape1 exonuclease has a role during BER after both DNA repair synthesis and excision of the abasic deoxyribose-5-phosphate by polymerase beta (PMID:12857737)
• substrate determinants for the exonuclease activity of human apurinic endonuclease Ape1 (PMID:12860125)
• data presented support a model by which X-ray repair cross complementing protein 1 (XRCC1) will pass on the DNA intermediate from DNA glycosylase hOGG1 to the endonuclease APE1 (PMID:12933815)
• mutational analysis of the alpha8 loop supports and extends the conclusion of crystallographic studies that the loop is important for binding of AP.DNA and AP site incision (PMID:12966083)
• Ape1 possesses activity as a major 3(’)-5(’) exonuclease in leukemia U937 cells. (PMID:14521941)
• APE/ref-1 expression is not different in platinum-sensitive and platinum-refractory ovarian cancers (PMID:14581338)
• APE/Ref-1 mediated CD40 activation of PAX5 and EBF. (PMID:14594818)
• APE/Ref-1 expression level and intracellular localization is variable in different types of tumors compared to the corresponding non-malignant human tissue, the protein is thought to be a diagnostic and prognostic tumor marker–REVIEW (PMID:14599768)
• role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8. (PMID:14630715)
• Ape1 is involved in the nucleotide incision repair pathway (NIR), it incises DNA containing 5,6-dihydro-2’-pyrimidines, 5-hydroxy-2’-deoxyuridine, alpha-2’-deoxyadenosine and alpha-thymidine adducts, generating 3’-hydroxyl and 5’-phosphate termini. (PMID:14704345)
• Ape1, the major apurinic/apyrimidinic endonuclease in human cells, is the damage- specific endonuclease involved in nucleotide incision repair (PMID:14704345)
• Hydrogen bonds to phosphate groups downstream of the AP cleavage site are essential for APE1’s binding to the product DNA, which may be necessary for efficient functioning of the base excision repair pathway. (PMID:14730972)
• Presented evidence that APE1 also acts on AP sites in single-stranded (ss) DNA. (PMID:15084314)
• While nuclear base excision repair protein levels and activities were generally not altered in rho(0) cells, AP endonuclease activity was substantially reduced in nuclear and in whole cell extracts (PMID:15107486)
• significant correlation between high APE1 expression levels and reduced survival times in osteosarcoma (PMID:15210853)
• APE1 is the main enzyme responsible for removal of 3’-phosphoglycolate in human cell extracts. (PMID:15247342)
• APE/ref-1 plays a significant role in gemcitabine resistance in some pancreatic cancer cells. (PMID:15316562)
• The data show that H. pylori or reactive oxygen species enhance APE-1/Ref-1 protein synthesis and nuclear accumulation in human gastric epithelial cells and implicate APE-1/Ref-1 in the modulation of the pathogenesis of H. pylori infection. (PMID:15362040)
• roles of three conserved tyrosine residues in close proximity to the active site (PMID:15380100)
• Analysis of structural determinants of substrate specificity of human APE1. (PMID:15459284)
• A novel physiological role for APE1/ref-1 in regulating vascular tone by governance of eNOS activity and bioavailable NO. (PMID:15472121)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	apex1	ENSDARG00000045843
mus_musculus	Apex1	ENSMUSG00000035960
rattus_norvegicus	Apex1	ENSRNOG00000009663
drosophila_melanogaster	Rrp1	FBGN0004584
caenorhabditis_elegans	exo-3	WBGENE00001372

Paralogs (1): APEX2 (ENSG00000169188)

Protein

Protein identifiers

DNA repair nuclease/redox regulator APEX1 — P27695 (reviewed: P27695)

Alternative names: APEX nuclease, Apurinic-apyrimidinic endonuclease 1, DNA-(apurinic or apyrimidinic site) endonuclease, Redox factor-1

All UniProt accessions (13): P27695, A0A0C4DGK8, G3V2D9, G3V359, G3V3C7, G3V3M6, G3V3Y6, G3V574, G3V5D9, G3V5M0, G3V5Q1, H7C4A8, Q5TZP7

UniProt curated annotations — full annotation on UniProt →

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 an apurinic/apyrimidinic (AP) endodeoxyribonuclease in the 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. Also incises at AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of R-loop structures, and single-stranded RNA molecules. Operates at switch sites of immunoglobulin (Ig) constant regions where it mediates Ig isotype class switch recombination. Processes AP sites induced by successive action of AICDA and UNG. Generates staggered nicks in opposite DNA strands resulting in the formation of double-strand DNA breaks that are finally resolved via non-homologous end joining repair pathway. Has 3’-5’ exodeoxyribonuclease activity on mismatched deoxyribonucleotides at the 3’ termini of nicked or gapped DNA molecules during short-patch BER. Possesses DNA 3’ phosphodiesterase activity capable of removing lesions (such as phosphoglycolate and 8-oxoguanine) blocking the 3’ side of DNA strand breaks. Also acts 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. 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. 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. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. Stimulates the YBX1-mediated MDR1 promoter activity, when acetylated at Lys-6 and Lys-7, leading to drug resistance. Plays a role in protection from granzyme-mediated cellular repair leading to cell death. Binds DNA and RNA. Associates, together with YBX1, on the MDR1 promoter. Together with NPM1, associates with rRNA.

Subunit / interactions. Monomer. Homodimer; disulfide-linked. Component of the SET complex, composed of at least APEX1, SET, ANP32A, HMGB2, NME1 and TREX1. Associates with the dimer XRCC5/XRCC6 in a DNA-dependent manner. Interacts with SIRT1; the interaction is increased in the context of genotoxic stress. Interacts with HDAC1, HDAC2 and HDAC3; the interactions are not dependent on the APEX1 acetylation status. Interacts with XRCC1; the interaction is induced by SIRT1 and increased with the APEX1 acetylated form. Interacts with NPM1 (via N-terminal domain); the interaction is RNA-dependent and decreases in hydrogen peroxide-damaged cells. Interacts (via N-terminus) with YBX1 (via C-terminus); the interaction is increased in presence of APEX1 acetylated at Lys-6 and Lys-7. Interacts with HNRNPL; the interaction is DNA-dependent. Interacts (via N-terminus) with KPNA1 and KPNA2. Interacts with TXN; the interaction stimulates the FOS/JUN AP-1 complex DNA-binding activity in a redox-dependent manner. Interacts with GZMA, KRT8, MDM2, PRDX6, PRPF19, RPLP0, TOMM20 and WDR77. Interacts with POLB. Binds to CDK5.

Subcellular location. Nucleus. Nucleolus. Nucleus speckle. Endoplasmic reticulum. Cytoplasm Mitochondrion.

Post-translational modifications. Phosphorylated. Phosphorylation by kinase PKC or casein kinase CK2 results in enhanced redox activity that stimulates binding of the FOS/JUN AP-1 complex to its cognate binding site. AP-endodeoxyribonuclease activity is not affected by CK2-mediated phosphorylation. Phosphorylation of Thr-233 by CDK5 reduces AP-endodeoxyribonuclease activity resulting in accumulation of DNA damage and contributing to neuronal death. Acetylated on Lys-6 and Lys-7. Acetylation is increased by the transcriptional coactivator EP300 acetyltransferase, genotoxic agents like H(2)O(2) and methyl methanesulfonate (MMS). Acetylation increases its binding affinity to the negative calcium response element (nCaRE) DNA promoter. The acetylated form induces a stronger binding of YBX1 to the Y-box sequence in the MDR1 promoter than the unacetylated form. Deacetylated on lysines. Lys-6 and Lys-7 are deacetylated by SIRT1. Cleaved at Lys-31 by granzyme A to create the mitochondrial form; leading to reduction of binding to DNA, AP endodeoxynuclease activity, redox activation of transcription factors and to enhanced cell death. Cleaved by granzyme K; leading to intracellular ROS accumulation and enhanced cell death after oxidative stress. Cys-65 and Cys-93 are nitrosylated in response to nitric oxide (NO) and lead to the exposure of the nuclear export signal (NES). Ubiquitinated by MDM2; leading to translocation to the cytoplasm and proteasomal degradation.

Activity regulation. NPM1 stimulates endodeoxyribonuclease activity on double-stranded DNA with AP sites, but inhibits endoribonuclease activity on single-stranded RNA containing AP sites.

Cofactor. Probably binds two magnesium or manganese ions per subunit.

Domain organisation. The N-terminus contains the redox activity while the C-terminus exerts the DNA AP-endodeoxyribonuclease activity; both functions are independent in their actions. An unconventional mitochondrial targeting sequence (MTS) is harbored within the C-terminus, that appears to be masked by the N-terminal sequence containing the nuclear localization signal (NLS), that probably blocks the interaction between the MTS and Tom proteins.

Induction. Up-regulated in presence of reactive oxygen species (ROS), like bleomycin, H(2)O(2) and phenazine methosulfate.

Miscellaneous. Extract of mitochondria, but not of nuclei or cytosol, cleaves recombinant APEX1 to generate a mitochondrial APEX1-sized product. The specific activity of the cleaved mitochondrial endodeoxyribonuclease appears to be about 3-fold higher than that of the full-length form.

Similarity. Belongs to the DNA repair enzymes AP/ExoA family.

RefSeq proteins (4): NP_001231178, NP_001632, NP_542379, NP_542380 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004808	AP_endonuc_1	Family
IPR005135	Endo/exonuclease/phosphatase	Domain
IPR020847	AP_endonuclease_F1_BS	Binding_site
IPR020848	AP_endonuclease_F1_CS	Conserved_site
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily

Pfam: PF03372

Enzyme classification (BRENDA):

• EC 4.2.99.18 — DNA-(apurinic or apyrimidinic site) lyase (BRENDA: 46 organisms, 543 substrates, 374 inhibitors, 166 Km, 138 kcat entries)

Substrate kinetics (BRENDA)

68 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
5’-CTCTCCCTTC-5,6-DIHYDROURACIL-CTCCTTTCCTCT-3'	—	13
DNA CONTAINING AN ABASIC SITE	100–413	9
5’-GACAAGCGCAG-(5R,6S)-2’-DEOXY-5,6-DIHYDROXYURI	—	8
DNA CONTAINING 5-OH-C/A	—	6
5’-GACAAGCGCAG-(5S,6R)-2’-DEOXY-5,6-DIHYDROXYURI	—	5
DNA CONTAINING 5-OH-C/G	—	5
OLIGOMER WITH G/U PAIR	0.0001–0.0013	5
43-MER OLIGONUCLEOTIDE CONTAINING APURINIC/APYRI	—	4
5’-CTCTCCCTTC-8-OXO-7,8-DIHYDROGUANINE-CTCCTTTCC	0.0006–0.0013	4
AP-DNA	0.0001–0.011	4
DNA	0.0009–0.0017	4
DNA CONTAINING APURINIC/APYRIMIDINIC SITES	—	4
THF-CONTAINING OLIGONUCLEOTIDE	0.0001–0.0002	4
12-MER OLIGODEOXYRIBONUCLEOTIDE CONTAINING A NAT	0.0001–0.0002	2
18-MER CONTAINING P33-LABELED TETRAHYDROFURAN	—	2

Catalyzed reactions (Rhea), 3 shown:

• a 3’-end 2’-deoxyribonucleotide-3’-phosphoglycolate-DNA + H2O = 2-phosphoglycolate + a 3’-end 2’-deoxyribonucleotide-DNA + H(+) (RHEA:81467)
• a 3’-end 2’-deoxyribonucleotide-8-oxoguanine-DNA + H2O = 8-oxo-dGMP + a 3’-end 2’-deoxyribonucleotide-DNA + H(+) (RHEA:81471)
• a deoxyribonucleotide-2’-deoxyribose-5’-monophosphate-DNA + H2O = a 5’-end 2’-deoxyribose-5’-monophosphate-DNA + a 3’-end 2’-deoxyribonucleotide-DNA + H(+) (RHEA:81527)

UniProt features (108 total): mutagenesis site 33, strand 18, helix 14, modified residue 12, binding site 6, site 4, region of interest 4, active site 3, sequence variant 3, chain 2, short sequence motif 2, sequence conflict 2, turn 2, initiator methionine 1, disulfide bond 1, compositionally biased region 1

Structure

Experimental structures (PDB)

67 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7TC3	X-RAY DIFFRACTION	1.25
4QHE	X-RAY DIFFRACTION	1.4
7TC2	X-RAY DIFFRACTION	1.43
6MKK	X-RAY DIFFRACTION	1.44
6MK3	X-RAY DIFFRACTION	1.48
5DFF	X-RAY DIFFRACTION	1.57
6BOW	X-RAY DIFFRACTION	1.59
7MEV	X-RAY DIFFRACTION	1.6
5DFI	X-RAY DIFFRACTION	1.63
4QHD	X-RAY DIFFRACTION	1.65
6MKM	X-RAY DIFFRACTION	1.67
9RQS	X-RAY DIFFRACTION	1.7
5CFG	X-RAY DIFFRACTION	1.8
5DG0	X-RAY DIFFRACTION	1.8
6BOR	X-RAY DIFFRACTION	1.84
5DFJ	X-RAY DIFFRACTION	1.85
6W0Q	X-RAY DIFFRACTION	1.89
2O3H	X-RAY DIFFRACTION	1.9
7MCR	X-RAY DIFFRACTION	1.9
4LND	X-RAY DIFFRACTION	1.92
6W2P	X-RAY DIFFRACTION	1.94
5DFH	X-RAY DIFFRACTION	1.95
1HD7	X-RAY DIFFRACTION	1.95
6BOQ	X-RAY DIFFRACTION	1.96
6BOV	X-RAY DIFFRACTION	1.98
6W43	X-RAY DIFFRACTION	1.99
7LPH	X-RAY DIFFRACTION	1.99
7SUV	X-RAY DIFFRACTION	1.99
9DP2	X-RAY DIFFRACTION	1.99
5WN3	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27695-F1	90.97	0.85

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (7): 171; 210 (proton donor/acceptor); 309 (proton acceptor); 31–32 (cleavage; by granzyme a); 212 (transition state stabilizer); 283 (important for catalytic activity); 309 (interaction with dna substrate)

Ligand- & substrate-binding residues (6): 68; 96; 210; 212; 308; 309

Post-translational modifications (12): 6, 7, 27, 31, 32, 35, 54, 65, 93, 197, 233, 310

Disulfide bonds (1): 65–93

Mutagenesis-validated functional residues (33):

Position	Phenotype
6	lack of acetylation, does not stimulate the ybx1-mediated mdr1 promoter activity and alter nuclear subcellular localizat
7	lack of acetylation and does not stimulate the ybx1-mediated mdr1 promoter activity and alter nuclear subcellular locali
12	reduces nuclear localization; when associated with a-13.
13	reduces nuclear localization; when associated with a-12.
24	enhances the interaction with tomm20. inhibits rrna binding, interaction with npm1, nuclear localization and modulates i
25	enhances the interaction with tomm20. inhibits rrna binding, interaction with npm1, nuclear localization and modulates i
27	enhances the interaction with tomm20. inhibits rrna binding, interaction with npm1, nuclear localization and modulates i
31	enhances the interaction with tomm20. does not inhibit redox and ap endodeoyribonuclease activities. inhibits rrna bindi
32	inhibits rrna binding, interaction with npm1, nuclear localization and modulates its endodeoxyribonuclease activity; whe
65	abolishes the redox activity. does not abolish the ap endodeoxyribonuclease and phosphodiesterase activities. reduces pr
65	does not abolish no-induced nitrosylation. enhances no-induced nuclear export.
68	nearly abolishes ap endodeoxyribonuclease activity.
70	strongly reduces ap endodeoxyribonuclease activity.
93	abolishes partially the redox activity.
93	does not abolish no-induced nitrosylation. abolishes no-induced nitrosylation and translocation from the nucleus to the
96	lacks myc crd rna cleavage activity.
99	does not abolish the redox activity.
138	does not abolish the redox activity.
171	abolishes the ap endodeoxyribonuclease activity.
208	does not abolish the redox activity.
210	abolishes the ap endodeoxyribonuclease activity. reduces protection from granzyme a-mediated cell death; when associated
212	abolishes ap endodeoxyribonuclease activity.
212	decreases ap endodeoxyribonuclease activity.
266	strongly reduces ap endodeoxyribonuclease activity.
283	strongly reduces ap endodeoxyribonuclease activity, but does not affect rna cleavage activity. nearly abolishes ap endod

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-110357	Displacement of DNA glycosylase by APEX1
R-HSA-110362	POLB-Dependent Long Patch Base Excision Repair
R-HSA-110373	Resolution of AP sites via the multiple-nucleotide patch replacement pathway
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair
R-HSA-73930	Abasic sugar-phosphate removal via the single-nucleotide replacement pathway
R-HSA-73933	Resolution of Abasic Sites (AP sites)
R-HSA-110381	Resolution of AP sites via the single-nucleotide replacement pathway
R-HSA-73884	Base Excision Repair
R-HSA-73894	DNA Repair

MSigDB gene sets: 565 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8_TCELL_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GOBP_CHROMOSOME_ORGANIZATION, GOBP_HINDBRAIN_DEVELOPMENT, MODULE_52, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, HARRIS_HYPOXIA

GO Biological Process (14): telomere maintenance (GO:0000723), DNA repair (GO:0006281), base-excision repair (GO:0006284), base-excision repair, gap-filling (GO:0006287), DNA catabolic process (GO:0006308), DNA recombination (GO:0006310), regulation of apoptotic process (GO:0042981), regulation of mRNA stability (GO:0043488), positive regulation of gene expression via chromosomal CpG island demethylation (GO:0044029), cell redox homeostasis (GO:0045454), positive regulation of transcription by RNA polymerase II (GO:0045944), telomere maintenance via base-excision repair (GO:0097698), DNA damage response (GO:0006974), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (29): DNA binding (GO:0003677), damaged DNA binding (GO:0003684), double-stranded telomeric DNA binding (GO:0003691), transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), RNA binding (GO:0003723), DNA-(apurinic or apyrimidinic site) endonuclease activity (GO:0003906), endonuclease activity (GO:0004519), DNA endonuclease activity (GO:0004520), RNA-DNA hybrid ribonuclease activity (GO:0004523), phosphodiesterase I activity (GO:0004528), uracil DNA N-glycosylase activity (GO:0004844), phosphoric diester hydrolase activity (GO:0008081), 3’-5’-DNA exonuclease activity (GO:0008296), double-stranded DNA exodeoxyribonuclease activity (GO:0008309), double-stranded DNA 3’-5’ DNA exonuclease activity (GO:0008311), 3’-5’ exonuclease activity (GO:0008408), oxidoreductase activity (GO:0016491), chromatin DNA binding (GO:0031490), deoxyribonuclease (pyrimidine dimer) activity (GO:0033892), metal ion binding (GO:0046872), class II DNA-(apurinic or apyrimidinic site) endonuclease activity (GO:0052720), phosphodiesterase activity, acting on 3’-phosphoglycolate-terminated DNA strands (GO:0090580), DNA-(abasic site) binding (GO:0140431), catalytic activity (GO:0003824), nuclease activity (GO:0004518), exonuclease activity (GO:0004527), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (11): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), centrosome (GO:0005813), ribosome (GO:0005840), nuclear speck (GO:0016607), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Resolution of Abasic Sites (AP sites)	3
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	2
Resolution of AP sites via the single-nucleotide replacement pathway	1
Base Excision Repair	1
DNA Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	5
intracellular membrane-bounded organelle	3
cellular anatomical structure	3
cytoplasm	3
base-excision repair	2
DNA nuclease activity	2
positive regulation of DNA-templated transcription	2
nucleic acid binding	2
DNA binding	2
transcription coregulator activity	2
DNA endonuclease activity	2
exonuclease activity	2
DNA exonuclease activity, producing 5’-phosphomonoesters	2
nuclear lumen	2
intracellular membraneless organelle	2
telomere organization	1
DNA damage response	1
DNA repair	1
nucleic acid catabolic process	1
apoptotic process	1
regulation of programmed cell death	1
regulation of RNA stability	1
regulation of mRNA catabolic process	1
transcription initiation-coupled chromatin remodeling	1
cellular homeostasis	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
telomere maintenance in response to DNA damage	1
cellular response to stress	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
double-stranded DNA binding	1
telomeric repeat DNA binding	1
negative regulation of DNA-templated transcription	1
nuclease activity	1
endonuclease activity	1
RNA endonuclease activity producing 5’-phosphomonoesters, hydrolytic mechanism	1
phosphoric diester hydrolase activity	1
deaminated base DNA N-glycosylase activity	1

Protein interactions and networks

STRING

3594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APEX1	XRCC1	P18887	999
APEX1	ANP32A	P39687	995
APEX1	FEN1	P39748	989
APEX1	NME1	P15531	980
APEX1	LIG1	P18858	978
APEX1	POLB	P06746	971
APEX1	OGG1	P78554	969
APEX1	LIG3	P49916	968
APEX1	PNKP	Q96T60	916
APEX1	UNG	P13051	913
APEX1	PARP1	P09874	912
APEX1	GADD45A	P24522	911
APEX1	TP53	P04637	885
APEX1	APTX	Q7Z2E3	875
APEX1	MUTYH	Q9UIF7	870

IntAct

89 interactions, top by confidence:

A	B	Type	Score
EP300	APEX1	psi-mi:“MI:0915”(physical association)	0.720
EP300	APEX1	psi-mi:“MI:0192”(acetylation reaction)	0.720
EP300	APEX1	psi-mi:“MI:0407”(direct interaction)	0.720
HSPA1A	APEX1	psi-mi:“MI:0407”(direct interaction)	0.700
HSPA1A	APEX1	psi-mi:“MI:0915”(physical association)	0.700
APEX1	SIRT1	psi-mi:“MI:0915”(physical association)	0.620
SIRT1	APEX1	psi-mi:“MI:0403”(colocalization)	0.620
SIRT1	APEX1	psi-mi:“MI:0407”(direct interaction)	0.620
APEX1	KLHL36	psi-mi:“MI:0915”(physical association)	0.560
NFE2L2	APEX1	psi-mi:“MI:0915”(physical association)	0.510
Rnf4	APEX1	psi-mi:“MI:0914”(association)	0.500
Rnf4	APEX1	psi-mi:“MI:0915”(physical association)	0.500
	SP1	psi-mi:“MI:0915”(physical association)	0.500
MUTYH	APEX1	psi-mi:“MI:0407”(direct interaction)	0.440
TXN	APEX1	psi-mi:“MI:0407”(direct interaction)	0.440
APEX1	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
SRPK1	APEX1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
NPY2R	APEX1	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
APEX1	YBX1	psi-mi:“MI:0915”(physical association)	0.400
APEX1	XRCC1	psi-mi:“MI:0915”(physical association)	0.400
APEX1	TERF1	psi-mi:“MI:0915”(physical association)	0.370
TERF2	APEX1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (1417): APEX1 (Affinity Capture-Western), POLB (Two-hybrid), POLB (Reconstituted Complex), APEX1 (Biochemical Activity), APEX1 (Affinity Capture-Western), APEX1 (Affinity Capture-Western), APEX1 (Affinity Capture-Western), APEX1 (Biochemical Activity), APEX1 (Biochemical Activity), APEX1 (Affinity Capture-Western), SIRT1 (Affinity Capture-Western), APEX1 (Affinity Capture-Western), APEX1 (Affinity Capture-MS), APEX1 (Affinity Capture-MS), KPNA3 (Affinity Capture-MS)

ESM2 similar proteins: A0MTA1, A1YES6, A1YFZ3, A2T6Y4, A2T7I6, A3M208, A8J2Z9, A8XL25, B0V4U0, B0X4N8, B2I3E2, B7I5G4, O26314, O43049, P00388, P00389, P04175, P08967, P0A2X3, P0A2X4, P0C1I1, P13217, P23196, P26639, P26882, P27695, P28352, P36776, P37039, P37040, P37454, P43138, P51173, P93655, Q0UI56, Q16775, Q16T79, Q28333, Q388N2, Q3SYT8

Diamond homologs: A0A509ADV9, A1YES6, A1YFZ3, A2T6Y4, A2T7I6, O97240, P27695, Q5XF07, A0MTA1, F4JNY0, O26314, P0A2X3, P0A2X4, P23196, P27864, P28352, P37454, P43138, P45951, P51173, P87175, Q68G58, P09030, P44318, Q5E9N9, Q6DDT4, Q9UBZ4, P0A1A9, P0A1B0

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
ERCC6	“down-regulates activity”	APEX1	binding
APEX1	“down-regulates quantity by repression”	CYP11B2	“transcriptional regulation”
APEX1	“up-regulates quantity by expression”	SLC5A5	“transcriptional regulation”
CDK5	“up-regulates activity”	APEX1	phosphorylation
PRKN	“down-regulates quantity by destabilization”	APEX1	ubiquitination
MDM2	“down-regulates quantity by destabilization”	APEX1	ubiquitination
CSNK2A1	“up-regulates activity”	APEX1	phosphorylation
APEX1	“up-regulates quantity by expression”	TG	“transcriptional regulation”
APEX1	up-regulates	Base-excision_repair

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cellular Senescence	7	15.5×	2e-04
Transcriptional Regulation by TP53	6	6.0×	1e-02
Cellular responses to stress	10	5.9×	8e-04
Cellular responses to stimuli	10	5.1×	2e-03
Infectious disease	10	4.0×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
base-excision repair	5	30.0×	7e-04
positive regulation of blood vessel endothelial cell migration	5	25.1×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

194 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	133
Likely benign	26
Benign	17

Top pathogenic / likely-pathogenic (0)

SpliceAI

890 predictions. Top by Δscore:

Variant	Effect	Δscore
14:20454564:CCAA:C	donor_gain	1.0000
14:20455912:A:AG	acceptor_gain	1.0000
14:20455913:G:GG	acceptor_gain	1.0000
14:20456080:GAT:G	donor_gain	1.0000
14:20456099:GAT:G	donor_gain	1.0000
14:20456102:G:GG	donor_gain	1.0000
14:20456660:A:AG	acceptor_gain	1.0000
14:20456661:C:G	acceptor_gain	1.0000
14:20456664:A:AG	acceptor_gain	1.0000
14:20456664:ACAGT:A	acceptor_gain	1.0000
14:20456665:C:G	acceptor_gain	1.0000
14:20456666:A:AG	acceptor_gain	1.0000
14:20456666:AG:A	acceptor_loss	1.0000
14:20456666:AGT:A	acceptor_gain	1.0000
14:20456666:AGTG:A	acceptor_gain	1.0000
14:20456666:AGTGG:A	acceptor_gain	1.0000
14:20456667:G:GT	acceptor_gain	1.0000
14:20456667:GT:G	acceptor_gain	1.0000
14:20456667:GTG:G	acceptor_gain	1.0000
14:20456667:GTGG:G	acceptor_gain	1.0000
14:20456667:GTGGG:G	acceptor_gain	1.0000
14:20456797:G:GT	donor_gain	1.0000
14:20456798:A:T	donor_gain	1.0000
14:20456855:GCA:G	donor_gain	1.0000
14:20456857:ATAG:A	donor_loss	1.0000
14:20456860:GGTGA:G	donor_loss	1.0000
14:20456861:G:GC	donor_loss	1.0000
14:20456862:T:G	donor_loss	1.0000
14:20456986:TATA:T	acceptor_loss	1.0000
14:20456988:TAG:T	acceptor_loss	1.0000

AlphaMissense

2052 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:20456054:T:A	W67R	1.000
14:20456054:T:C	W67R	1.000
14:20457180:A:T	D210V	1.000
14:20457187:T:A	N212K	1.000
14:20457187:T:G	N212K	1.000
14:20457245:T:C	F232L	1.000
14:20457247:C:A	F232L	1.000
14:20457247:C:G	F232L	1.000
14:20457312:G:T	R254M	1.000
14:20457347:T:C	F266L	1.000
14:20457349:T:A	F266L	1.000
14:20457349:T:G	F266L	1.000
14:20457389:T:A	W280R	1.000
14:20457389:T:C	W280R	1.000
14:20456057:A:G	N68D	0.999
14:20456058:A:C	N68T	0.999
14:20456059:T:A	N68K	0.999
14:20456059:T:G	N68K	0.999
14:20456067:G:A	G71E	0.999
14:20456708:A:T	E96V	0.999
14:20457113:T:A	W188R	0.999
14:20457113:T:C	W188R	0.999
14:20457177:G:A	G209E	0.999
14:20457180:A:C	D210A	0.999
14:20457180:A:G	D210G	0.999
14:20457181:C:A	D210E	0.999
14:20457181:C:G	D210E	0.999
14:20457210:T:A	L220H	0.999
14:20457345:C:T	T265I	0.999
14:20457350:T:A	W267R	0.999

dbSNP variants (sampled 300 via entrez): RS1000814795 (14:20454049 C>A), RS1001209361 (14:20454012 C>CT), RS1001360753 (14:20455058 G>A), RS1001429585 (14:20455207 T>C,G), RS1001883961 (14:20457680 GTTTT>G,GT,GTTTTT), RS1002463226 (14:20456180 G>C,T), RS1003039464 (14:20456944 T>C), RS1004505521 (14:20453753 G>A), RS1004618509 (14:20453526 CCAGTT>C), RS1005242850 (14:20454519 T>C,G), RS1005375385 (14:20457642 G>A,C), RS1006213174 (14:20455785 C>A,T), RS1006389929 (14:20456689 G>A), RS1006656243 (14:20455435 G>A), RS1006791857 (14:20456369 G>GCATTC)

Disease associations

OMIM: gene MIM:107748 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Limited	Autosomal dominant

Mondo (3): breast ductal adenocarcinoma (MONDO:0005590), head and neck cancer (MONDO:0005627), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001674_2	Esophageal cancer (squamous cell)	3.000000e-16
GCST003398_3	Developmental language disorder (syntactic complexity)	5.000000e-06
GCST005312_33	Menopause (age at onset)	2.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007799	syntactic complexity measurement
EFO:0004704	age at menopause

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5619 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

53 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 844,014 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1010	CEFOTAXIME SODIUM	4	4,928
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1134	DECAMETHONIUM BROMIDE	4	1,096
CHEMBL1200411	ROPINIROLE HYDROCHLORIDE	4	5,547
CHEMBL1200522	AVOBENZONE	4	34,067
CHEMBL1200636	CYCLOBENZAPRINE HYDROCHLORIDE	4	3,894
CHEMBL1200714	CHLORMEZANONE	4	2,121
CHEMBL1201043	CEPHAPIRIN SODIUM	4	3,301
CHEMBL121663	DEQUALINIUM CHLORIDE	4	4,224
CHEMBL1240	PROPANTHELINE BROMIDE	4	5,250
CHEMBL1417019	MITOXANTRONE HYDROCHLORIDE	4	69,932
CHEMBL1423	PIMOZIDE	4	17,310
CHEMBL1437	NOREPINEPHRINE	4	108,675
CHEMBL1472989	BISOPROLOL FUMARATE	4	10,035
CHEMBL1531864	PIRENZEPINE HYDROCHLORIDE	4	3,874
CHEMBL1533310	HISTAMINE DIHYDROCHLORIDE	4	8,186
CHEMBL1568057	METAPROTERENOL SULFATE	4	6,315
CHEMBL160	CYCLOSPORINE	4	168,247
CHEMBL178	DAUNORUBICIN	4	203,756
CHEMBL30	CIMETIDINE	4	47,191
CHEMBL311498	CIANIDANOL	4
CHEMBL34259	METHOTREXATE	4
CHEMBL435	HYDROCHLOROTHIAZIDE	4
CHEMBL459	METHYLDOPA	4
CHEMBL56367	NIMESULIDE	4
CHEMBL585	TRIAMTERENE	4
CHEMBL59	DOPAMINE	4
CHEMBL856	PRIMIDONE	4
CHEMBL914	FEXOFENADINE	4
CHEMBL932	DIPYRIDAMOLE	4

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1760944	Efficacy	3	cisplatin;fluorouracil;radiotherapy	Carcinoma;Squamous Cell;Overall survival

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1130409	APEX1, OSGEP		0.00	0
rs2307486	APEX1, OSGEP		0.00	0
rs1760944	APEX1, OSGEP	3	2.25	1	cisplatin;fluorouracil;radiotherapy

Binding affinities (BindingDB)

50 measured of 77 human assays (77 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[dihydroxy(oxo)–stibanyl]-2-nitrobenzoic acid	IC50	4 nM
ethyl 4-{4-[dihydroxy(oxo)–stibanyl]phenyl}butanoate	IC50	17 nM
(2E)-3-{3-[dihydroxy(oxo)–stibanyl]phenyl}prop-2-enoic acid	IC50	200 nM
N-{4-[dihydroxy(oxo)–stibanyl]phenyl}benzamide	IC50	300 nM
NSC332397	KI	640 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
NSC332389	IC50	2900 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
2-{5-[(3Z)-1-(carboxymethyl)-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl}-3-phenylpropanoic acid	IC50	3000 nM
3-[1-(carboxymethyl)-5-(4-chlorophenyl)-1H-pyrrol-2-yl]propanoic acid	IC50	4000 nM
4-({4-[(4-carboxyphenyl)sulfanyl]benzene}sulfonyl)benzene-1,2-dicarboxylic acid	IC50	4000 nM
2-(2-{4-[1-(carboxymethyl)-1H-1,3-benzodiazol-2-yl]butyl}-1H-1,3-benzodiazol-1-yl)acetic acid	IC50	4000 nM
NSC332395	IC50	4100 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
NSC332398	IC50	4400 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
NSC614430	KI	4900 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
5-{[(2-{[(4-carboxy-5-methylfuran-2-yl)methyl]sulfanyl}ethyl)sulfanyl]methyl}-2-methylfuran-3-carboxylic acid	IC50	5000 nM
3-{5-[(3Z)-1-(carboxymethyl)-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl}propanoic acid	IC50	6000 nM
4-(2-carboxyphenoxymethyl)-2,5-dimethylfuran-3-carboxylic acid	IC50	6000 nM
3-(5-{[(5E)-3-(carboxymethyl)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl}furan-2-yl)benzoic acid	IC50	6000 nM
4-({4-[(4-carboxybenzene)sulfonyl]phenyl}sulfanyl)benzene-1,2-dicarboxylic acid	IC50	6000 nM
2-{3-[(5Z)-3-(4-bromophenyl)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}acetic acid	IC50	6000 nM
5-({[(4-carboxy-5-methylfuran-2-yl)methyl]sulfanyl}methyl)-3-methylfuran-2-carboxylic acid	IC50	6000 nM
NSC131534	KI	6700 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
4-{[4-(4-carboxyphenoxy)benzene]sulfonyl}benzene-1,2-dicarboxylic acid	IC50	6970 nM
2-{[3-(1-carboxyethoxy)-9-oxo-8-oxatricyclo[8.4.0.0^{2,7}]tetradeca-1(14),2(7),3,5,10,12-hexaen-5-yl]oxy}propanoic acid	IC50	8000 nM
2-(5-{[2-(2-carboxyphenyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]carbonyl}-1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)benzoic acid	IC50	8000 nM
3-[1-(carboxymethyl)-5-(thiophen-2-yl)-1H-pyrrol-2-yl]propanoic acid	IC50	9000 nM
2-{2-oxo-3-[(5Z)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]-2,3-dihydro-1H-indol-1-yl}acetic acid	IC50	9000 nM
NSC332384	IC50	10100 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
NSC300598	KI	10900 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
2-[10-(carboxymethyl)-6,12-dioxo-5,11-dioxatricyclo[7.3.0.0^{3,7}]dodeca-1,3(7),8-trien-4-yl]acetic acid	IC50	11000 nM
2-{3-[(5Z)-3-[(2-hydroxybenzene)amido]-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}acetic acid	IC50	11000 nM
3-(3,4-dimethylphenoxymethyl)furan-2-carboxylic acid	IC50	11000 nM
4-{5-[(3Z)-1-(carboxymethyl)-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl}butanoic acid	IC50	12000 nM
3-[1-(carboxymethyl)-5-(4-methylphenyl)-1H-pyrrol-2-yl]propanoic acid	IC50	12000 nM
2-{3-[(5Z)-3-(carboxymethyl)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}acetic acid	IC50	13000 nM
NSC89640	KI	13000 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
3-({[4-(carboxymethyl)phenyl]methyl}sulfanyl)-8-methyl-5H-[1,2,4]triazino[5,6-b]indole-5-carboxylic acid	IC50	15000 nM
3-[3-(2-carboxyethyl)-2-sulfanylidene-2,3-dihydro-1H-1,3-benzodiazol-1-yl]propanoic acid	IC50	15000 nM
2-[3-(carboxymethyl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl]acetic acid	IC50	16000 nM
2-methyl-5-{[(oxolan-2-ylmethyl)sulfanyl]methyl}furan-3-carboxylic acid	IC50	16000 nM
3-({5-[(2-carboxyethyl)sulfanyl]-1,3,4-thiadiazol-2-yl}sulfanyl)propanoic acid	IC50	17000 nM
NSC107215	KI	17000 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
2-({2-[(carboxymethyl)sulfanyl]-6-phenylpyrimidin-4-yl}sulfanyl)acetic acid	IC50	19000 nM
4-({[(3-carboxy-5-methylfuran-2-yl)methyl]sulfanyl}methyl)-5-methylfuran-2-carboxylic acid	IC50	20000 nM
3-(2-carboxyethyl)-4-hydroxy-2-methylquinoline-6-carboxylic acid	IC50	20000 nM
3-[(6-amino-9H-purin-8-yl)sulfanyl]propanoic acid	IC50	20000 nM
4-{[(2-carboxy-2-methylethyl)sulfanyl]methyl}-5-methylfuran-2-carboxylic acid	IC50	22000 nM
2-({4-[(carboxymethyl)carbamoyl]-2,5-dimethylfuran-3-yl}formamido)acetic acid	IC50	26000 nM
3-[(pyridin-2-ylsulfanyl)methyl]-1-benzofuran-2-carboxylic acid	IC50	27000 nM
NSC332396	IC50	34400 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity
NSC402686	KI	37000 nM	US-9624235: Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity

ChEMBL bioactivities

439 potent at pChembl≥5 of 942 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.06	Kd	0.88	nM	TANSHINONE IIA
8.96	Potency	1.1	nM	CHEMBL1323786
8.89	Potency	1.3	nM	CHEMBL1566820
8.89	Potency	1.3	nM	CHEMBL1305422
8.85	Potency	1.4	nM	CHEMBL3210521
8.85	Potency	1.4	nM	CHEMBL1432717
8.80	Kd	1.6	nM	APX-3330
8.74	Potency	1.8	nM	CHEMBL1410367
8.70	Potency	2	nM	CHEMBL3197141
8.66	Potency	2.2	nM	CHEMBL1971760
8.66	Potency	2.2	nM	CHEMBL1391063
8.60	Potency	2.5	nM	CHEMBL1611306
8.60	Potency	2.5	nM	CHEMBL1465659
8.55	Potency	2.8	nM	CHEMBL1321148
8.49	Potency	3.2	nM	CHEMBL1450895
8.46	Potency	3.5	nM	CHEMBL1409844
8.46	Potency	3.5	nM	CHEMBL1451059
8.35	Potency	4.5	nM	CHEMBL1994685
8.20	Potency	6.3	nM	CHEMBL1500249
8.20	Potency	6.3	nM	CHEMBL1441170
8.10	Potency	7.9	nM	CHEMBL3145010
8.00	Kd	10	nM	HYCANTHONE
8.00	Potency	10	nM	CHEMBL1538023
8.00	Potency	10	nM	CHEMBL1610567
7.85	Potency	14.1	nM	ELLAGIC ACID
7.80	Potency	15.8	nM	CHEMBL1576814
7.77	IC50	17	nM	CHEMBL1394152
7.55	Potency	28.2	nM	CHEMBL1404357
7.45	Potency	35.5	nM	CHEMBL3196993
7.40	Potency	39.8	nM	RAUWOLSCINE HYDROCHLORIDE
7.35	Potency	44.7	nM	CHEMBL1358777
7.30	Potency	50.1	nM	CHEMBL1331939
7.30	Potency	50.1	nM	CHEMBL1425538
7.26	IC50	55	nM	AURINTRICARBOXYLIC ACID
7.26	IC50	55	nM	CHEMBL4210534
7.25	Potency	56.2	nM	AURINTRICARBOXYLIC ACID
7.25	Potency	56.2	nM	CHEMBL1524472
7.24	IC50	57	nM	CHEMBL4205402
7.20	Potency	63.1	nM	CHEMBL1322274
7.20	Potency	63.1	nM	CHEMBL1307297
7.14	Kd	72.87	nM	CHEMBL5653589
7.14	ED50	72.87	nM	CHEMBL5653589
7.10	IC50	80	nM	HYCANTHONE
7.05	Kd	89	nM	LUCANTHONE
7.05	Potency	89.1	nM	CHEMBL311663
7.00	Potency	100	nM	CHEMBL3191714
6.96	IC50	110	nM	CHEMBL109037
6.95	Potency	112.2	nM	CHEMBL109037
6.92	Ki	120	nM	CHEMBL4216250
6.90	Potency	125.9	nM	CHEMBL1601846

PubChem BioAssay actives

156 with measured affinity, of 544 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1,6,6-trimethyl-8,9-dihydro-7H-naphtho[1,2-g][1]benzofuran-10,11-dione	1370992: Binding affinity to full length human APE1 expressed in Escherichia coli BL21/DE3	kd	0.0009	uM
(2E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)methylidene]undecanoic acid	1370994: Binding affinity to APE1 (unknown origin) by SPR assay	kd	0.0016	uM
1-[2-(diethylamino)ethylamino]-4-(hydroxymethyl)thioxanthen-9-one	1370992: Binding affinity to full length human APE1 expressed in Escherichia coli BL21/DE3	kd	0.0100	uM
2-nitro-4-stibonobenzoic acid	1798712: High-Throughput Screening and IC50 Determinations from Article 10.1124/mol.107.042622: “Potent inhibition of human apurinic/apyrimidinic endonuclease 1 by arylstibonic acids.”	ki	0.0190	uM
[4-(4-ethoxy-4-oxobutyl)phenyl]stibonic acid	1798712: High-Throughput Screening and IC50 Determinations from Article 10.1124/mol.107.042622: “Potent inhibition of human apurinic/apyrimidinic endonuclease 1 by arylstibonic acids.”	ki	0.0360	uM
5-[(3-carboxy-4-hydroxyphenyl)-(3-carboxy-4-oxocyclohexa-2,5-dien-1-ylidene)methyl]-2-hydroxybenzoic acid	1370986: Inhibition of human APE1 preincubated for 15 mins followed by substrate addition by HTS assay	ic50	0.0550	uM
6,22-dioxa-3,9,19,25-tetrazapentacyclo[25.5.3.311,17.030,34.014,37]octatriaconta-1(33),11(38),12,14(37),15,17(36),27(35),28,30(34),31-decaene	1370976: Inhibition of human APE1 assessed as reduction in abasic sites DNA cleavage using 6-FAM/TAMRA labelled 17-Tphi as substrate by fluorescence-based assay	ic50	0.0550	uM
3,6,9,19,22,25-hexazapentacyclo[25.5.3.311,17.030,34.014,37]octatriaconta-1(33),11(38),12,14(37),15,17(36),27(35),28,30(34),31-decaene	1370976: Inhibition of human APE1 assessed as reduction in abasic sites DNA cleavage using 6-FAM/TAMRA labelled 17-Tphi as substrate by fluorescence-based assay	ic50	0.0570	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147873: Binding affinity to human APEX1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0729	uM
1-[2-(diethylamino)ethylamino]-4-methylthioxanthen-9-one	1370992: Binding affinity to full length human APE1 expressed in Escherichia coli BL21/DE3	kd	0.0890	uM
2-amino-3-(2,4,5-trihydroxyphenyl)propanoic acid	1167344: Inhibition of human APE1 after 25 mins by fluorescence assay	ic50	0.1100	uM
(9-ethylcarbazol-3-yl)methyl-(6-methyl-[1,3]dioxolo[4,5-g]quinolin-8-yl)diazene	1799828: Molecular Beacon Assay from Article 10.1021/bi300490r: “Identification and characterization of human apurinic/apyrimidinic endonuclease-1 inhibitors.”	ki	0.1200	uM
1-methyl-4-[1-[(6-methyl-[1,3]dioxolo[4,5-g]quinolin-8-yl)diazenyl]ethyl]-2-phenylpyrazol-3-one	1799828: Molecular Beacon Assay from Article 10.1021/bi300490r: “Identification and characterization of human apurinic/apyrimidinic endonuclease-1 inhibitors.”	ki	0.1800	uM
1,3-benzodioxol-5-ylmethyl-(6-methyl-[1,3]dioxolo[4,5-g]quinolin-8-yl)diazene	1799828: Molecular Beacon Assay from Article 10.1021/bi300490r: “Identification and characterization of human apurinic/apyrimidinic endonuclease-1 inhibitors.”	ki	0.1900	uM
1,2,3-tribromo-5-(3,4,5-tribromophenyl)benzene	1370977: Inhibition of nuclease activity of APE1 in human glioblastoma cells assessed as reduction in AP site DNA cleavage	ic50	0.2000	uM
(E)-3-(3-stibonophenyl)prop-2-enoic acid	1798712: High-Throughput Screening and IC50 Determinations from Article 10.1124/mol.107.042622: “Potent inhibition of human apurinic/apyrimidinic endonuclease 1 by arylstibonic acids.”	ic50	0.2000	uM
(3-methoxyphenyl)methyl-(6-methyl-[1,3]dioxolo[4,5-g]quinolin-8-yl)diazene	1799828: Molecular Beacon Assay from Article 10.1021/bi300490r: “Identification and characterization of human apurinic/apyrimidinic endonuclease-1 inhibitors.”	ki	0.2200	uM
5-[(E)-2-(4-acetamido-2-sulfonatophenyl)ethenyl]-2-isothiocyanatobenzenesulfonate	1802172: Fluorescence-Based APE1 Endonuclease Activity Assay from Article 10.1111/cbdd.12826: “Structure-based virtual screening toward the discovery of novel inhibitors of the DNA repair activity of the human apurinic/apyrimidinic endonuclease 1.”	ic50	0.2500	uM
disodium;5-[(E)-2-(4-acetamido-2-sulfonatophenyl)ethenyl]-2-isothiocyanatobenzenesulfonate	1370985: Inhibition of recombinant human APE1 using double-stranded DNA as substrate preincubated for 15 mins followed by substrate addition measured at 1 min intervals for 30 mins by fluorescence-based assay	ic50	0.2500	uM
1-amino-4-[4-[[4-chloro-6-(4-sulfoanilino)-1,3,5-triazin-2-yl]amino]-3-sulfoanilino]-9,10-dioxoanthracene-2-sulfonic acid	1167344: Inhibition of human APE1 after 25 mins by fluorescence assay	ic50	0.2500	uM
trisodium;1-amino-4-[4-[[4-chloro-6-(4-sulfonatoanilino)-1,3,5-triazin-2-yl]amino]-3-sulfonatoanilino]-9,10-dioxoanthracene-2-sulfonate	1370986: Inhibition of human APE1 preincubated for 15 mins followed by substrate addition by HTS assay	ic50	0.2500	uM
(E)-2-(3,4-dihydroxybenzoyl)-3-(3,4-dihydroxyphenyl)prop-2-enenitrile	1370986: Inhibition of human APE1 preincubated for 15 mins followed by substrate addition by HTS assay	ic50	0.2800	uM
(4-benzamidophenyl)stibonic acid	1798712: High-Throughput Screening and IC50 Determinations from Article 10.1124/mol.107.042622: “Potent inhibition of human apurinic/apyrimidinic endonuclease 1 by arylstibonic acids.”	ic50	0.3000	uM
3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)chromen-4-one	1167344: Inhibition of human APE1 after 25 mins by fluorescence assay	ic50	0.3200	uM
2,3,9,10-tetrahydroxypyrano[3,2-c]isochromene-6,8-dione	1370982: Inhibition of human APE1 using a 5’-TAMRA labelled THF abasic site double-stranded oligodeoxynucleotide as substrate in presence of Mg2+ by fluorescence polarization displacement assay	ic50	0.4000	uM
3,6,7-trimethoxyphenanthrene-2,5-diol	1370982: Inhibition of human APE1 using a 5’-TAMRA labelled THF abasic site double-stranded oligodeoxynucleotide as substrate in presence of Mg2+ by fluorescence polarization displacement assay	ic50	0.4000	uM
N-(3,4-dihydroxyphenyl)-N-methylnitrous amide	1370986: Inhibition of human APE1 preincubated for 15 mins followed by substrate addition by HTS assay	ic50	0.5000	uM
1,5-dimethyl-4-[[(6-methyl-[1,3]dioxolo[4,5-g]quinolin-8-yl)diazenyl]methyl]-2-phenylpyrazol-3-one	1799828: Molecular Beacon Assay from Article 10.1021/bi300490r: “Identification and characterization of human apurinic/apyrimidinic endonuclease-1 inhibitors.”	ki	0.6800	uM
(2,4-ditert-butylphenyl) 3-chloro-1-benzothiophene-2-carboxylate	1370977: Inhibition of nuclease activity of APE1 in human glioblastoma cells assessed as reduction in AP site DNA cleavage	ic50	0.8000	uM
N-(3,5-dichlorophenyl)-4-[4-(2-fluorophenyl)phenyl]-5-methyl-1,3-thiazol-2-amine	1370977: Inhibition of nuclease activity of APE1 in human glioblastoma cells assessed as reduction in AP site DNA cleavage	ic50	0.9000	uM
(5R)-4-hydroxy-3,5-dimethyl-5-[(1E)-2-methylbuta-1,3-dienyl]thiophen-2-one	1370986: Inhibition of human APE1 preincubated for 15 mins followed by substrate addition by HTS assay	ic50	1.0000	uM
(E)-3-(3-chloro-1,4-dioxonaphthalen-2-yl)-N-(2-hydroxyethyl)-2-methylprop-2-enamide	444047: Inhibition of Ape1/ref-1 redox activity in presence of 0.02 mM DTT and human Hey-C2 cells nuclear extracts by EMSA	ic50	1.0000	uM
(E)-3-(3-chloro-1,4-dioxonaphthalen-2-yl)-2-methylprop-2-enoic acid	444047: Inhibition of Ape1/ref-1 redox activity in presence of 0.02 mM DTT and human Hey-C2 cells nuclear extracts by EMSA	ic50	1.0000	uM
(E)-3-(3-methoxy-1,4-dioxonaphthalen-2-yl)-2-methylprop-2-enoic acid	444047: Inhibition of Ape1/ref-1 redox activity in presence of 0.02 mM DTT and human Hey-C2 cells nuclear extracts by EMSA	ic50	1.0000	uM
(E)-2-methyl-3-(3-methylsulfanyl-1,4-dioxonaphthalen-2-yl)prop-2-enoic acid	444047: Inhibition of Ape1/ref-1 redox activity in presence of 0.02 mM DTT and human Hey-C2 cells nuclear extracts by EMSA	ic50	1.0000	uM
(2E)-2-[(3-bromo-1,4-dioxonaphthalen-2-yl)methylidene]-4-methoxybutanoic acid	444047: Inhibition of Ape1/ref-1 redox activity in presence of 0.02 mM DTT and human Hey-C2 cells nuclear extracts by EMSA	ic50	1.0000	uM
N-[3-(1,3-benzothiazol-2-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl]acetamide	672546: Inhibition of recombinant APE1 using [35P]-5’-AP-DNA as substrate incubated for 15 mins prior to substrate addition measured after 5 mins by PAGE analysis	ic50	1.0000	uM
(7S,10R,11S,12E)-7-(1H-indol-3-ylmethyl)-11-methyl-10-[1-(4-methylphenyl)sulfonylpyrrol-2-yl]-4-phenyl-1-oxa-6,9-diazacyclopentadec-12-ene-5,8,15-trione	1614383: Inhibition of full length human APE1 assessed as reduction in endonuclease activity by measuring DNA cleavage of abasic sites using 6-FAM labelled two annealed oligonucleotides as AP site mimic substrate by fluorescence-based assay	ic50	1.2000	uM
(3S,7S,11E,13S,14R)-3-(1H-indol-3-ylmethyl)-13-methyl-14-[1-(4-methylphenyl)sulfonylpyrrol-2-yl]-7-[4-(trifluoromethyl)phenyl]-1,4,8-triazacyclotetradec-11-ene-2,5,9-trione	1614383: Inhibition of full length human APE1 assessed as reduction in endonuclease activity by measuring DNA cleavage of abasic sites using 6-FAM labelled two annealed oligonucleotides as AP site mimic substrate by fluorescence-based assay	ic50	1.3000	uM
2-(4-chlorophenyl)-4-[4-(2-fluorophenyl)phenyl]-5-methyl-1,3-thiazole	1370977: Inhibition of nuclease activity of APE1 in human glioblastoma cells assessed as reduction in AP site DNA cleavage	ic50	1.3000	uM
2-aminobenzene-1,3,5-trisulfonamide	1370979: Inhibition of human APE1 measured every 5 mins for 60 mins by FAM fluorophore based fluorescence assay	ic50	1.4000	uM
(3-chloro-1-benzothiophen-2-yl)-[2-(2-chlorophenyl)imino-4-methylidene-3-thia-1-azaspiro[4.5]decan-1-yl]methanone	1370977: Inhibition of nuclease activity of APE1 in human glioblastoma cells assessed as reduction in AP site DNA cleavage	ic50	1.4000	uM
2,4,9-trimethylbenzo[b][1,8]naphthyridin-5-amine	672582: Inhibition of human APE1 expressed in Escherichia coli rosetta using fluorescein-dabcyl-containing oligonucleotide as substrate after 5 mins by fluorescence spectrophotometry	ic50	1.5000	uM
N-(3-chlorophenyl)-5,6-dihydro-4H-cyclopenta[d][1,2]oxazole-3-carboxamide	1370980: Inhibition of N-terminal hexa-His tagged human APE1 expressed in Escherichia coli BL21 (Rosetta) using fluorescein-dabcyl-containing oligonucleotide as substrate measured over 5 mins by high-throughput fluorescence assay	ic50	1.6000	uM
7-chloro-2-(2-fluorophenyl)-3,1-benzoxazin-4-one	1370977: Inhibition of nuclease activity of APE1 in human glioblastoma cells assessed as reduction in AP site DNA cleavage	ic50	1.6000	uM
[4-[4-(2-chloro-6-nitrophenoxy)phenyl]phenyl] 4-tert-butylbenzenesulfonate	1370977: Inhibition of nuclease activity of APE1 in human glioblastoma cells assessed as reduction in AP site DNA cleavage	ic50	1.7000	uM
2-[(Z)-(4-hydroxy-3-methylphenyl)-(3-methyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl]benzoic acid	1370979: Inhibition of human APE1 measured every 5 mins for 60 mins by FAM fluorophore based fluorescence assay	ic50	1.7000	uM
2-[4-(2,5-dimethylpyrrol-1-yl)phenoxy]acetic acid	1370980: Inhibition of N-terminal hexa-His tagged human APE1 expressed in Escherichia coli BL21 (Rosetta) using fluorescein-dabcyl-containing oligonucleotide as substrate measured over 5 mins by high-throughput fluorescence assay	ic50	1.7000	uM
3-[(1R,3S,3aS,6aR)-5-(1,3-benzodioxol-5-ylmethyl)-7’-chloro-2’,4,6-trioxospiro[1,2,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-3,3’-1H-indole]-1-yl]propanoic acid	1370981: Inhibition of recombinant human APE1 using a 5’-FAM/3’-Dabsyl labelled double-stranded DNA as substrate after 30 mins by fluorescence-based assay	ic50	1.8000	uM
(7S,10R,11S,12E)-4-(1,3-benzodioxol-5-yloxy)-7-(1H-indol-3-ylmethyl)-11-methyl-10-phenyl-1-oxa-6,9-diazacyclopentadec-12-ene-5,8,15-trione	1614383: Inhibition of full length human APE1 assessed as reduction in endonuclease activity by measuring DNA cleavage of abasic sites using 6-FAM labelled two annealed oligonucleotides as AP site mimic substrate by fluorescence-based assay	ic50	1.8000	uM

CTD chemical–gene interactions

92 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects response to substance, decreases reaction, increases mutagenesis, increases response to substance, increases expression (+1 more)	5
arsenite	increases reaction, increases expression, affects expression, affects localization, affects binding	4
Carmustine	increases response to substance, decreases response to substance	4
Temozolomide	increases response to substance, decreases response to substance	3
Cisplatin	decreases response to substance, affects binding, increases reaction, decreases expression, increases acetylation (+1 more)	3
Hydrogen Peroxide	decreases activity, decreases reaction, increases response to substance, increases expression	3
Lead	affects response to substance, decreases activity, decreases reaction, affects expression	3
Methyl Methanesulfonate	decreases expression, increases response to substance, decreases response to substance	3
Oxygen	increases expression, increases reaction, decreases expression, decreases reaction	3
Valproic Acid	decreases expression, affects expression	3
cobaltous chloride	decreases expression, affects binding, increases activity, increases reaction	2
E 3330	decreases activity, decreases reaction	2
Air Pollutants	decreases expression, increases abundance, increases methylation	2
Arsenic	affects response to substance	2
Benzene	affects response to substance, affects expression	2
Dacarbazine	increases response to substance, decreases response to substance	2
Enzyme Inhibitors	decreases activity, decreases expression, increases O-linked glycosylation	2
Floxuridine	increases response to substance, decreases response to substance	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Sodium Selenite	affects cotreatment, affects localization, decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases methylation	2
FR900359	decreases phosphorylation	1
pradimicin-IRD	affects expression, affects response to substance	1
bisphenol A	increases expression, increases reaction	1
lead acetate	increases expression, increases reaction, increases phosphorylation, decreases response to substance, affects binding (+1 more)	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
trichostatin A	increases acetylation, affects binding, increases reaction	1
hesperetin	affects binding	1
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1

ChEMBL screening assays

49 unique, capped per target: 45 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1021377	Binding	Inhibition of purified human recombinant APE1 expressed in Escherichia coli M15 cells	Pharmacophore guided discovery of small-molecule human apurinic/apyrimidinic endonuclease 1 inhibitors. — J Med Chem
CHEMBL1614211	Functional	PubChem BioAssay. qHTS Assay for Inhibitors of the Human Apurinic/apyrimidinic Endonuclease 1 (APE1). (Class of assay: confirmatory)	PubChem BioAssay data set

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 3 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B0WA	HEK293-FT APEX1 KO clone 1C4	Transformed cell line	Female
CVCL_B0WB	HEK293-FT APEX1 KO clone 2A9	Transformed cell line	Female
CVCL_B9DE	Abcam A-549 APEX1 KO	Cancer cell line	Male
CVCL_D7K7	Ubigene A-549 APEX1 KO	Cancer cell line	Male
CVCL_D8Z9	Ubigene HEK293 APEX1 KO	Transformed cell line	Female
CVCL_DX28	HAP1 APEX1 (-) XPA (-)	Cancer cell line	Male
CVCL_KT31	HeLa SilenciX APE1	Cancer cell line	Female
CVCL_SC92	HAP1 APEX1 (-) 1	Cancer cell line	Male
CVCL_XL38	HAP1 APEX1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

600 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00138827	PHASE4	COMPLETED	Mouth Care Regimes During Radiotherapy
NCT00158041	PHASE4	COMPLETED	Subcutaneous Amifostine Safety Study
NCT00198263	PHASE4	COMPLETED	Study Using the Medpulser Electroporation System With Bleomycin to Treat Head and Neck Cancer
NCT00333099	PHASE4	COMPLETED	INEC Study: Immuno-modulating Enteral Nutrition in Cancer
NCT00365508	PHASE4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00666978	PHASE4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT00772681	PHASE4	COMPLETED	Efficacy of Chemoradiotherapy After Neoadjuvant Cisplatin and Docetaxel in the Nasopharynx Carcinoma
NCT00813631	PHASE4	UNKNOWN	The Effect on an Ionic Silver Dressing in Head and Neck Patients With Malignant Fungating Wound
NCT01317589	PHASE4	COMPLETED	Treatment of Pain in Head-and-Neck Cancer Patients: is Methadone More Effective?
NCT01418118	PHASE4	COMPLETED	Assessment of the Effects of Pressors on Graft Blood Flow After Free Tissue Transfer Surgery
NCT01553032	PHASE4	COMPLETED	Skin Changes in Head and Neck Cancer During Immuno-(Chemo-) And Radiotherapy With Erbitux® (HICARE)
NCT02015650	PHASE4	TERMINATED	Cetuximab Compared to Mitomycin-C and 5-Fluorouracil for Locally Advanced Squamous Cell Carcinomas of the Head and Neck
NCT02049112	PHASE4	COMPLETED	A New Oral salIvary equivAlent Compared to Two moisturizinG Mouth sprAys in Patients With xeRostomiA: NIAGARA Study
NCT02241083	PHASE4	COMPLETED	The Effect of Norepinephrine and Dopamine on Radial Forearm Free Flap Tissue Oxygen Pressure and Microdialysate Metabolite Measurements
NCT02241876	PHASE4	UNKNOWN	THE USE OF N-ACETYLCYSTEINE ATTENUATING CISPLATIN-INDUCED TOXICITIES BY OXIDATIVE STRESS
NCT02597582	PHASE4	COMPLETED	LigaSure Small Jaw® Versus Conventional Neck Dissection in Head and Neck Cancer Patients
NCT02622880	PHASE4	COMPLETED	Comparison of Two Immunomodulatory Formulas on the Number of Postoperative Infections in Head & Neck Cancer Patients
NCT02880072	PHASE4	COMPLETED	Absorption of Orally Ingested Phosphate in Refeeding Syndrome
NCT02926573	PHASE4	COMPLETED	Perioperative Gabapentin Use In Head And Neck Mucosal Surgery Patients
NCT03607227	PHASE4	COMPLETED	Continous Popliteal Block for Microvascular Free Flap Reconstruction in Ear, Nose and Throat Surgery
NCT03714867	PHASE4	WITHDRAWN	Pre-Operative Pregabalin for Post-Operative Pain in Head and Neck Cancer Surgery
NCT04155008	PHASE4	TERMINATED	Nutrition and Pharmacological Algorithm for Oncology Patients Study
NCT04246697	PHASE4	COMPLETED	Multimodal Pain Study in Free Flap Patients
NCT04292990	PHASE4	UNKNOWN	Comparison of Transdermal Fentanyl and Morphine for Oral Mucositis Pain in Nasopharyngeal Cancer Patients
NCT04507035	PHASE4	UNKNOWN	Treating Locally Advanced Head and Neck Malignant Tumor With Anlotinib and Chemoradiotherapy
NCT04977271	PHASE4	WITHDRAWN	Mood Disorders in Head and Neck Cancer Patients
NCT05046028	PHASE4	COMPLETED	Individualization of Nutritive Sensory Support Of Radiation Therapy
NCT05055726	PHASE4	COMPLETED	Benzydamine Oromucosal Solution in Oral Mucositis (BOOM)
NCT06521697	PHASE4	NOT_YET_RECRUITING	Effects of Minimal-Flow Sevoflurane and Multimodal Analgesia in Head and Neck Cancer Surgery
NCT06734598	PHASE4	RECRUITING	Efficacy of Botox Injection of the Masticatory Muscles in Head &Neck Cancer Patients with Trismus After Radiotherapy
NCT06807034	PHASE4	ACTIVE_NOT_RECRUITING	Impact of the Oral Microbiota on Relapse in HNSCC Patients
NCT06879691	PHASE4	ACTIVE_NOT_RECRUITING	A Trial of Nimotuzumab and Pinkiller Efficacy and Pain in Advanced Head and Neck Squamous Cell Carcinoma
NCT07158164	PHASE4	RECRUITING	DPYD Pharmacogenomics and Fluoropyrimidine (FP) Dose-Adjustment
NCT07189897	PHASE4	RECRUITING	Apixaban or Enoxaparin After Head and Neck Cancer Surgery