FEN1

Summary

FEN1 (flap structure-specific endonuclease 1, HGNC:3650) is a protein-coding gene on chromosome 11q12.2, encoding Flap endonuclease 1 (P39748). Structure-specific nuclease with 5’-flap endonuclease and 5’-3’ exonuclease activities involved in DNA replication and repair. It is a selective cancer dependency (DepMap: 86.8% of cell lines).

The protein encoded by this gene removes 5’ overhanging flaps in DNA repair and processes the 5’ ends of Okazaki fragments in lagging strand DNA synthesis. Direct physical interaction between this protein and AP endonuclease 1 during long-patch base excision repair provides coordinated loading of the proteins onto the substrate, thus passing the substrate from one enzyme to another. The protein is a member of the XPG/RAD2 endonuclease family and is one of ten proteins essential for cell-free DNA replication. DNA secondary structure can inhibit flap processing at certain trinucleotide repeats in a length-dependent manner by concealing the 5’ end of the flap that is necessary for both binding and cleavage by the protein encoded by this gene. Therefore, secondary structure can deter the protective function of this protein, leading to site-specific trinucleotide expansions.

Source: NCBI Gene 2237 — RefSeq curated summary.

At a glance

• GWAS associations: 91
• Clinical variants (ClinVar): 40 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 86.8% of screened cell lines
• MANE Select transcript: NM_004111

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3650
Approved symbol	FEN1
Name	flap structure-specific endonuclease 1
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Aliases	FEN-1, MF1
Ensembl gene	ENSG00000168496
Ensembl biotype	protein_coding
OMIM	600393
Entrez	2237

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000305885, ENST00000535307, ENST00000535723, ENST00000925117, ENST00000925118, ENST00000967695

RefSeq mRNA: 1 — MANE Select: NM_004111 NM_004111

CCDS: CCDS8010

Canonical transcript exons

ENST00000305885 — 2 exons

Exon	Start	End
ENSE00001224079	61792911	61793028
ENSE00001327269	61795341	61797238

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 97.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.5856 / max 254.1520, expressed in 1776 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114610	26.5856	1776

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	97.72	gold quality
oocyte	CL:0000023	94.29	gold quality
cervix squamous epithelium	UBERON:0006922	94.23	silver quality
amniotic fluid	UBERON:0000173	93.91	gold quality
paraflocculus	UBERON:0005351	93.72	gold quality
gingival epithelium	UBERON:0001949	92.39	gold quality
secondary oocyte	CL:0000655	92.07	gold quality
squamous epithelium	UBERON:0006914	92.06	gold quality
esophagus squamous epithelium	UBERON:0006920	91.52	gold quality
tendon of biceps brachii	UBERON:0008188	91.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.31	gold quality
trabecular bone tissue	UBERON:0002483	91.25	gold quality
bone marrow	UBERON:0002371	91.20	gold quality
embryo	UBERON:0000922	91.11	gold quality
endothelial cell	CL:0000115	91.06	gold quality
ventricular zone	UBERON:0003053	90.95	gold quality
bone element	UBERON:0001474	90.89	gold quality
sperm	CL:0000019	90.33	silver quality
ganglionic eminence	UBERON:0004023	90.30	gold quality
bone marrow cell	CL:0002092	90.05	gold quality
frontal pole	UBERON:0002795	89.84	gold quality
epithelium of esophagus	UBERON:0001976	89.83	gold quality
mucosa of transverse colon	UBERON:0004991	89.66	gold quality
choroid plexus epithelium	UBERON:0003911	89.60	gold quality
middle frontal gyrus	UBERON:0002702	89.25	gold quality
hair follicle	UBERON:0002073	88.83	silver quality
tongue squamous epithelium	UBERON:0006919	88.83	silver quality
epithelium of nasopharynx	UBERON:0001951	88.54	gold quality
nasopharynx	UBERON:0001728	88.53	gold quality
gingiva	UBERON:0001828	88.46	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-99795	yes	431.27
E-ENAD-27	yes	341.32
E-MTAB-7052	yes	240.76
E-GEOD-100618	yes	83.92
E-HCAD-10	yes	24.97
E-ANND-3	yes	7.52
E-MTAB-6911	no	818.98
E-MTAB-9689	no	153.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, ESR2, GLI2, TP53, ZNF143

miRNA regulators (miRDB)

35 targeting FEN1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-4727-5P	99.23	67.55	1154
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4711-3P	98.97	66.87	1020
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-3929	98.32	65.58	1026

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 86.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Direct physical interaction between FEN1 and AP endonuclease 1 during long-patch base excision repair provides coordinated loading of the proteins onto the substrate, thus passing the substrate from one enzyme to another. (PMID:11601988)
• DNA ligase I competes with FEN1 to expand repetitive DNA sequences in vitro. (PMID:11948189)
• Arginine residues 47 and 70 are involved in DNA substrate interactions and cleavage site determination (PMID:11986308)
• the rate of excision by FEN-1 of 5’-flaps from short- and long-flap oligonucleotide substrates that mimic pre- and post-repair HIV-1 integration intermediates, respectively, and the effect of HIV-1 integrase on these reactions were examined (PMID:12065902)
• stimulated by APE1 for progression through the base excision repair pathway (PMID:12200445)
• interaction of the WRN gene product with human 5’ flap endonuclease/5’-3’ exonuclease (FEN-1) (PMID:12356323)
• flexible loop is important for efficient cleavage through positioning the 5’ flap and the catalytic site (PMID:12411510)
• Single nucleotide polymorphism in exon 15 of the XPG gene exhibited marginally significant increased frequency of the variant allele compared to controls. (PMID:12494477)
• This protein can procss the 5’-flap DNA of CTG/CAG triplet repeat derived from human genetic diseases. (PMID:12515398)
• human flap endonuclease 1 mutants employ endonuclease rather than exonuclease to prevent triplet repeat expansion (PMID:12554738)
• C-terminal lysines are important for the endonuclease and exonuclease activities likely through DNA binding (PMID:12683998)
• Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation. (PMID:12853968)
• action at DNA replication forks (PMID:12856420)
• We report here that faulty processing by FEN-1 initiates repeat instability in mammalian cells (PMID:12917330)
• Alterations of FEN1 are not likely to contribute to development of lung cancer. (PMID:14562054)
• WRN and FEN-1 proteins function together to process DNA structures associated with the replication fork. (PMID:14657243)
• flap endonuclease-1 is stimulated by the Bloom’s syndrome protein (PMID:14688284)
• model for human FEN-1 protein interaction with its DNA substrates (PMID:15037610)
• substrate specificity of Fen1 has been functionally conserved over a billion years from archaea to human (PMID:15131255)
• identification of rad9-rad1-hus1 as a damage-specific activator of flap endonuclease 1 (PMID:15556996)
• pol beta cooperates with FEN1 to remove DNA damage via a “Hit and Run” mechanism, involving alternating short gap production by FEN1 and gap filling by pol beta (PMID:15561706)
• results suggest that BLM suppresses genome instability by aiding FEN1 cleavage of structure-containing flaps (PMID:15579905)
• a novel gap endonuclease (GEN) activity of human flap endonuclease 1 (FEN-1), critical in resolving stalled replication fork (PMID:15592449)
• The structural basis of the FEN1-PCNA interaction was revealed by the crystal structure of the complex between human FEN1 and proliferating cell nuclear antigen (PMID:15616578)
• Fen1 exchange depends on the rate of movement of replication forks. (PMID:15758026)
• A general DNA substrate-binding model that helps explains how the single active center of FEN-1 can perform cleavage on various substrates. (PMID:16582103)
• The rearrangement frequency was found to increase with array size, and partial complementation of the rad27Delta mutation by hFEN1 demonstrated that the production of novel CEB1 alleles is Rad52 and Rad51 dependent. (PMID:16914748)
• Both pol-beta and Fen-1 interact with a 138-amino-acid peptide from adenomatosis polyposis coli protein at the DNA repair inhibitory (DRI) domain. (PMID:17176113)
• endogenously expressed FEN-1 associates with the native pS2 gene in MCF-7 cells and influences estrogen-responsive gene expression (PMID:17488975)
• Asymmetric unit is predicted to contain two complexes in the crystallographic asymmetric unit. A diffraction data set was collected to a resolution of 2.75 A. (PMID:18097100)
• C-terminus of FEN-1 is important for protein binding (PMID:18291413)
• contributes to telomere stability by ensuring efficient telomere replication (PMID:18394896)
• The replacement of Ser(187) by Ala, eliminating the only phosphorylation site, retains FEN1 in nucleoli. (PMID:18443037)
• hChlR1 has a role in the establishment of sister chromatid cohesion, with Ctf18-RFC and Fen1 (PMID:18499658)
• Repair of 2-deoxyribonolactone is via long-patch BER (LP-BER) dependent on flap endonuclease 1 (FEN1) in mitochondria. (PMID:18541666)
• NEIL1 could also participate in strand displacement repair synthesis (long patch repair (LP-BER)) mediated by FEN-1 and stimulated by PCNA. (PMID:18662981)
• DENSPM treatment affects the cellular distribution of FEN1 in L56Br-C1 cells, but not in MCF-7 cells, implying that FEN1 is affected by or involved in DENSPM-induced apoptosis. (PMID:18786645)
• findings show that FEN1 is significantly up-regulated in multiple cancers and the aberrant expression of FEN1 is associated with hypomethylation of the CpG island within the FEN1 promoter in tumor cells (PMID:19010819)
• FEN1 and telomerase physically co-exist as a complex and that FEN1 can regulate telomerase activity at telomeres in mammalian cells. (PMID:19068479)
• Data show that replication factor C (RFC), via several stimulatory motifs per molecule, potently activates flap endonuclease 1 (FEN1), making RFC a critical partner with FEN1 for the processing of eukaryotic Okazaki fragments. (PMID:19208620)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fen1	ENSDARG00000011404
mus_musculus	Fen1	ENSMUSG00000024742
rattus_norvegicus	Fen1	ENSRNOG00000020531
drosophila_melanogaster	Fen1	FBGN0025832
caenorhabditis_elegans	crn-1	WBGENE00000794

Paralogs (2): EXO1 (ENSG00000174371), GEN1 (ENSG00000178295)

Protein

Protein identifiers

Flap endonuclease 1 — P39748 (reviewed: P39748)

Alternative names: DNase IV, Flap structure-specific endonuclease 1, Maturation factor 1

All UniProt accessions (4): P39748, F5H1Y3, I3L3E9, Q6FHX6

UniProt curated annotations — full annotation on UniProt →

Function. Structure-specific nuclease with 5’-flap endonuclease and 5’-3’ exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5’-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5’-end of a downstream Okazaki fragment. It enters the flap from the 5’-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structures that lead to duplications and deletions. Also possesses 5’-3’ exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA.

Subunit / interactions. Interacts with PCNA. Three molecules of FEN1 bind to one PCNA trimer with each molecule binding to one PCNA monomer. PCNA stimulates the nuclease activity without altering cleavage specificity. The C-terminal domain binds EP300; can bind simultaneously to both PCNA and EP300. Interacts with DDX11; this interaction is direct and increases flap endonuclease activity of FEN1. Interacts with WDR4; regulating its endonuclease activity. Interacts with POLB.

Subcellular location. Nucleus. Nucleolus. Nucleoplasm Mitochondrion.

Post-translational modifications. Acetylated by EP300. Acetylation inhibits both endonuclease and exonuclease activity. Acetylation also reduces DNA-binding activity but does not affect interaction with PCNA or EP300. Phosphorylation upon DNA damage induces relocalization to the nuclear plasma. Phosphorylation at Ser-187 by CDK2 occurs during late S-phase and results in dissociation from PCNA. Methylation at Arg-192 by PRMT5 impedes Ser-187 phosphorylation and increases interaction with PCNA.

Cofactor. Binds 2 magnesium ions per subunit. They probably participate in the reaction catalyzed by the enzyme. May bind an additional third magnesium ion after substrate binding.

Miscellaneous. No nuclease activity. Binds preferentially to RNA flap structures and R-loops.

Similarity. Belongs to the XPG/RAD2 endonuclease family. FEN1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P39748-1	1	yes
P39748-2	FENMIT

RefSeq proteins (1): NP_004102* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006084	XPG/Rad2	Family
IPR006085	XPG_DNA_repair_N	Domain
IPR006086	XPG-I_dom	Domain
IPR008918	HhH2	Conserved_site
IPR019974	XPG_CS	Conserved_site
IPR023426	Flap_endonuc	Family
IPR029060	PIN-like_dom_sf	Homologous_superfamily
IPR036279	5-3_exonuclease_C_sf	Homologous_superfamily

Pfam: PF00752, PF00867

Enzyme classification (BRENDA):

• EC 3.1.99.B1 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (85 total): helix 19, modified residue 16, mutagenesis site 16, binding site 12, strand 11, region of interest 4, turn 4, chain 1, splice variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
9RCI	X-RAY DIFFRACTION	1.66
1U7B	X-RAY DIFFRACTION	1.88
5ZOD	X-RAY DIFFRACTION	1.9
5ZOE	X-RAY DIFFRACTION	1.95
5E0V	X-RAY DIFFRACTION	2.07
5K97	X-RAY DIFFRACTION	2.1
5KSE	X-RAY DIFFRACTION	2.1
9RDI	X-RAY DIFFRACTION	2.1
3Q8K	X-RAY DIFFRACTION	2.2
5ZOF	X-RAY DIFFRACTION	2.25
5ZOG	X-RAY DIFFRACTION	2.3
3Q8L	X-RAY DIFFRACTION	2.32
3UVU	X-RAY DIFFRACTION	2.38
3Q8M	X-RAY DIFFRACTION	2.6
5UM9	X-RAY DIFFRACTION	2.81
5FV7	X-RAY DIFFRACTION	2.84
1UL1	X-RAY DIFFRACTION	2.9
8YJL	ELECTRON MICROSCOPY	3.51
8YJQ	ELECTRON MICROSCOPY	3.51
8YJR	ELECTRON MICROSCOPY	3.51
8YJV	ELECTRON MICROSCOPY	3.51
8YJS	ELECTRON MICROSCOPY	3.55
8YJW	ELECTRON MICROSCOPY	3.55
8YJH	ELECTRON MICROSCOPY	3.68
8YJU	ELECTRON MICROSCOPY	3.78
6TNZ	ELECTRON MICROSCOPY	4.05
7QO1	ELECTRON MICROSCOPY	4.4
8YJZ	ELECTRON MICROSCOPY	5.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P39748-F1	90.00	0.84

Functional residue map

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

Ligand- & substrate-binding residues (12): 158; 158; 160; 179; 181; 231; 233; 233; 34; 47; 70; 86

Post-translational modifications (16): 19, 80, 100, 104, 187, 192, 197, 255, 293, 335, 336, 354, 364, 375, 377, 380

Mutagenesis-validated functional residues (16):

Position	Phenotype
29	no significant effect on exonuclease activity or flap endonuclease activity.
34	loss of flap endonuclease activity but substrate binding activity is retained.
47	significantly reduced exonuclease activity and reduced substrate binding. the positions of the cleavage sites are also s
70	loss of exonuclease activity and reduced endonuclease activity. reduced substrate binding.
73	no significant effect on exonuclease activity or flap endonuclease activity.
80	no significant effect on exonuclease activity or flap endonuclease activity.
86	loss of flap endonuclease activity but substrate binding activity is retained.
103	no effect on flap endonuclease activity or substrate binding.
158	loss of flap endonuclease activity and substrate binding.
179	no effect on flap endonuclease activity or substrate binding.
181	loss of flap endonuclease activity but substrate binding activity is retained.
187	fails to translocate from nucleoli to the nuclear plasma.
187	diminishes nucleolar localization.
192	impairs ability to localize to sites of dna replication or repair.
231	loss of flap endonuclease activity and substrate binding.
233	loss of flap endonuclease activity and substrate binding.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-110362	POLB-Dependent Long Patch Base Excision Repair
R-HSA-162594	Early Phase of HIV Life Cycle
R-HSA-174437	Removal of the Flap Intermediate from the C-strand
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair
R-HSA-5685939	HDR through MMEJ (alt-NHEJ)
R-HSA-69166	Removal of the Flap Intermediate

MSigDB gene sets: 453 (showing top): GOBP_MEMORY, GOBP_CHROMOSOME_ORGANIZATION, KALMA_E2F1_TARGETS, REACTOME_DNA_REPLICATION, MODULE_52, RRAGTTGT_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GNF2_MSH2, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, MODULE_451, GOBP_COGNITION, MORF_ESPL1, TSENG_IRS1_TARGETS_UP, GNF2_CENPF

GO Biological Process (13): double-strand break repair via homologous recombination (GO:0000724), DNA replication (GO:0006260), DNA repair (GO:0006281), base-excision repair, gap-filling (GO:0006287), double-strand break repair (GO:0006302), memory (GO:0007613), UV protection (GO:0009650), telomere maintenance via semi-conservative replication (GO:0032201), DNA replication, removal of RNA primer (GO:0043137), positive regulation of sister chromatid cohesion (GO:0045876), base-excision repair (GO:0006284), DNA recombination (GO:0006310), DNA damage response (GO:0006974)

GO Molecular Function (19): magnesium ion binding (GO:0000287), DNA binding (GO:0003677), damaged DNA binding (GO:0003684), double-stranded DNA binding (GO:0003690), endonuclease activity (GO:0004519), RNA-DNA hybrid ribonuclease activity (GO:0004523), exonuclease activity (GO:0004527), double-stranded DNA exodeoxyribonuclease activity (GO:0008309), 5’-3’ exonuclease activity (GO:0008409), 5’-flap endonuclease activity (GO:0017108), manganese ion binding (GO:0030145), flap endonuclease activity (GO:0048256), catalytic activity (GO:0003824), nuclease activity (GO:0004518), DNA endonuclease activity (GO:0004520), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on ester bonds (GO:0016788), metal ion binding (GO:0046872)

GO Cellular Component (7): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), mitochondrion (GO:0005739), membrane (GO:0016020), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	2
HIV Life Cycle	1
Processive synthesis on the C-strand of the telomere	1
Homology Directed Repair	1
Processive synthesis on the lagging strand	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	4
DNA repair	2
DNA binding	2
nuclease activity	2
hydrolase activity, acting on ester bonds	2
intracellular membrane-bounded organelle	2
nuclear lumen	2
cellular anatomical structure	2
recombinational repair	1
double-strand break repair	1
DNA biosynthetic process	1
DNA damage response	1
base-excision repair	1
learning or memory	1
response to UV	1
telomere maintenance	1
cell cycle process	1
nuclear DNA replication	1
DNA replication	1
RNA catabolic process	1
sister chromatid cohesion	1
regulation of sister chromatid cohesion	1
positive regulation of cell cycle process	1
positive regulation of chromosome organization	1
cellular response to stress	1
metal ion binding	1
nucleic acid binding	1
RNA endonuclease activity producing 5’-phosphomonoesters, hydrolytic mechanism	1
DNA exonuclease activity, producing 5’-phosphomonoesters	1
exonuclease activity	1
DNA endonuclease activity, producing 5’-phosphomonoesters	1
flap endonuclease activity	1
transition metal ion binding	1
DNA endonuclease activity	1
molecular_function	1
catalytic activity, acting on a nucleic acid	1
endonuclease activity	1
DNA nuclease activity	1
binding	1
catalytic activity	1

Protein interactions and networks

STRING

4434 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FEN1	WRN	Q14191	991
FEN1	APEX1	P27695	989
FEN1	DNA2	P51530	975
FEN1	LIG1	P18858	973
FEN1	NEIL1	Q96FI4	962
FEN1	RECQL4	O94761	956
FEN1	ERCC1	P07992	939
FEN1	XPC	Q01831	910
FEN1	XRCC1	P18887	884
FEN1	POLB	P06746	857
FEN1	POLD1	P28340	856
FEN1	ERCC3	P19447	855
FEN1	RAD51	Q06609	849
FEN1	XPA	P23025	831
FEN1	XRCC5	P13010	824

IntAct

139 interactions, top by confidence:

A	B	Type	Score
PCNA	FEN1	psi-mi:“MI:0407”(direct interaction)	0.960
FEN1	PCNA	psi-mi:“MI:0407”(direct interaction)	0.960
FEN1	PCNA	psi-mi:“MI:0915”(physical association)	0.960
PCNA	FEN1	psi-mi:“MI:0915”(physical association)	0.960
FEN1	PCNA	psi-mi:“MI:2364”(proximity)	0.960
PCNA	FEN1	psi-mi:“MI:2364”(proximity)	0.960
WRN	FEN1	psi-mi:“MI:0915”(physical association)	0.820
WRN	FEN1	psi-mi:“MI:0407”(direct interaction)	0.820
FEN1	WRN	psi-mi:“MI:0407”(direct interaction)	0.820
WRN	FEN1	psi-mi:“MI:2364”(proximity)	0.820
WRN	FEN1	psi-mi:“MI:0403”(colocalization)	0.820
FEN1	WRN	psi-mi:“MI:0915”(physical association)	0.820
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
WDR4	FEN1	psi-mi:“MI:0915”(physical association)	0.660

BioGRID (324): FEN1 (Affinity Capture-RNA), FEN1 (Affinity Capture-RNA), FEN1 (Affinity Capture-RNA), FEN1 (Affinity Capture-Western), FEN1 (Affinity Capture-Western), FEN1 (Two-hybrid), FEN1 (Affinity Capture-MS), FEN1 (Affinity Capture-MS), PCNA (Affinity Capture-MS), DRG1 (Co-fractionation), FEN1 (Co-fractionation), FEN1 (Co-fractionation), FEN1 (Co-fractionation), FEN1 (Co-fractionation), FEN1 (Co-fractionation)

ESM2 similar proteins: A0B9M7, A0RU95, A0RX10, A2SQC6, A3CWV2, A4HFE4, A4QS18, A5ABU3, A5UL52, A6ZZK4, A7IA59, A7RRJ0, A7TJ59, A9A4B0, A9U328, A9VB27, B0DSN9, B0EN90, B3LQY3, B3RVF0, B4GIM3, B5DUR8, B8GIA0, B8MNF2, C4QZ20, C7GVJ8, C7Z125, C8BKD0, C8ZC62, O27670, P26793, P39748, P39749, Q013G9, Q0W6I0, Q12UT1, Q2FNC9, Q2FQH4, Q2NFD4, Q46CS0

Diamond homologs: A0B9M7, A0RU95, A1CJ75, A1D8A4, A1RSC7, A1RWY2, A2BMI0, A2SQC6, A3CWV2, A3DMG2, A3M056, A3MY15, A4QS18, A4WNC4, A5ABU3, A5DCF5, A5E121, A5UL52, A6QV55, A6UX46, A7IA59, A7RRJ0, A7TJ59, A7UW97, A8AAC1, A8M9L3, A9A4B0, B0DSN9, B0XZ33, B1H158, B1L6R9, B1YC46, B2VTT3, B3MDA3, B3RVF0, B4FHY0, B4KNM1, B4P5U9, B6HEM2, B6QT52

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CDK1	“down-regulates activity”	FEN1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 133 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
Resolution of D-loop Structures through Holliday Junction Intermediates	5	14.4×	3e-03
Signaling by ALK fusions and activated point mutants	6	8.7×	6e-03
mRNA Splicing	7	7.4×	5e-03
Processing of Capped Intron-Containing Pre-mRNA	9	7.1×	1e-03
DNA Repair	7	6.6×	7e-03
mRNA Splicing - Major Pathway	12	6.3×	3e-04
Transcriptional Regulation by TP53	9	5.4×	5e-03
Dengue Virus-Host Interactions	12	5.3×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
replication fork processing	6	20.7×	1e-04
telomere maintenance	8	17.5×	2e-05
double-strand break repair	7	11.7×	5e-04
DNA replication	6	8.1×	1e-02
mRNA splicing, via spliceosome	9	6.8×	1e-03
DNA repair	12	6.3×	1e-04
DNA damage response	11	4.8×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

263 predictions. Top by Δscore:

Variant	Effect	Δscore
11:61795338:TA:T	acceptor_loss	1.0000
11:61795339:A:AG	acceptor_gain	1.0000
11:61795339:AGTCA:A	acceptor_loss	1.0000
11:61795340:G:GG	acceptor_gain	1.0000
11:61795340:GT:G	acceptor_gain	1.0000
11:61795340:GTC:G	acceptor_gain	1.0000
11:61795340:GTCAT:G	acceptor_gain	1.0000
11:61793025:CCAGG:C	donor_loss	0.9900
11:61793026:CAG:C	donor_loss	0.9900
11:61793027:AG:A	donor_loss	0.9900
11:61793028:GGT:G	donor_loss	0.9900
11:61793029:GTG:G	donor_loss	0.9900
11:61793030:T:G	donor_loss	0.9900
11:61795340:GTCA:G	acceptor_gain	0.9900
11:61795338:TAG:T	acceptor_gain	0.9700
11:61795339:AG:A	acceptor_gain	0.9700
11:61795336:TTTAG:T	acceptor_gain	0.9600
11:61795337:TTA:T	acceptor_gain	0.9600
11:61795340:G:T	acceptor_gain	0.9600
11:61793043:G:T	donor_gain	0.9500
11:61795320:T:TA	acceptor_gain	0.9500
11:61794177:A:G	donor_gain	0.9400
11:61795064:A:AG	donor_gain	0.9400
11:61795335:TTTTA:T	acceptor_gain	0.9400
11:61795363:T:TA	acceptor_gain	0.9400
11:61792948:G:GT	donor_gain	0.9300
11:61793024:GCCAG:G	donor_gain	0.9300
11:61793029:G:GG	donor_gain	0.9300
11:61795364:G:A	acceptor_gain	0.9200
11:61792880:TC:T	donor_gain	0.9100

AlphaMissense

2508 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:61795447:G:C	R29P	0.999
11:61795485:T:C	F42L	0.999
11:61795487:C:A	F42L	0.999
11:61795487:C:G	F42L	0.999
11:61795557:G:C	G66R	0.999
11:61795558:G:A	G66D	0.999
11:61795570:G:C	R70P	0.999
11:61795612:T:A	V84D	0.999
11:61795640:G:C	K93N	0.999
11:61795640:G:T	K93N	0.999
11:61795792:T:C	L144P	0.999
11:61795850:T:G	C163W	0.999
11:61795896:G:C	D179H	0.999
11:61795897:A:C	D179A	0.999
11:61795897:A:T	D179V	0.999
11:61795898:C:A	D179E	0.999
11:61795898:C:G	D179E	0.999
11:61795456:C:A	A32D	0.998
11:61795465:C:A	A35D	0.998
11:61795473:A:C	S38R	0.998
11:61795475:C:A	S38R	0.998
11:61795475:C:G	S38R	0.998
11:61795489:T:C	L43P	0.998
11:61795495:C:A	A45D	0.998
11:61795569:C:A	R70S	0.998
11:61795579:G:C	R73P	0.998
11:61795603:C:A	P81H	0.998
11:61795603:C:G	P81R	0.998
11:61795614:T:C	F85L	0.998
11:61795616:T:A	F85L	0.998

dbSNP variants (sampled 300 via entrez): RS1000006148 (11:61796864 A>C,G), RS1001813317 (11:61794721 A>C), RS1002391793 (11:61794793 T>C), RS1002676540 (11:61792969 C>A,T), RS1002728911 (11:61793306 GCCTA>G), RS1003234090 (11:61791478 G>A,T), RS1004745993 (11:61795076 G>A,T), RS1005841801 (11:61794508 T>C), RS1006583422 (11:61792948 G>GGA), RS1007011508 (11:61794088 A>G), RS1007038240 (11:61791003 G>A), RS1008861845 (11:61797564 C>T), RS1009021746 (11:61791201 C>G,T), RS1009060165 (11:61793940 G>A), RS1010078730 (11:61793722 A>G)

Disease associations

OMIM: gene MIM:600393 | disease phenotypes: MIM:236750

GenCC curated gene-disease

Mondo (2): non-immune hydrops fetalis (MONDO:0009369), hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (2): Non-immune hydrops fetalis (Orphanet:363999), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

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

GWAS associations

91 associations (top):

Study	Trait	p-value
GCST001178_9	Plasma omega-3 polyunsaturated fatty acid level (eicosapentaenoic acid)	6.000000e-55
GCST001179_11	Plasma omega-3 polyunsaturated fatty acid levels (docosapentaenoic acid)	1.000000e-139
GCST001180_10	Plasma omega-3 polyunsaturated fatty acid levels (alphalinolenic acid)	9.000000e-60
GCST001337_32	Platelet count	3.000000e-10
GCST001834_5	Oleic acid (18:1n-9) levels	2.000000e-32
GCST001840_3	Stearic acid (18:0) levels	1.000000e-20
GCST001841_1	Palmitoleic acid (16:1n-7) levels	7.000000e-13
GCST001852_1	Metabolite levels	3.000000e-09
GCST002444_5	Plasma omega-6 polyunsaturated fatty acid levels (dihomo-gamma-linolenic acid)	5.000000e-168
GCST002446_1	Plasma omega-6 polyunsaturated fatty acid levels (linoleic acid)	4.000000e-274
GCST002446_7	Plasma omega-6 polyunsaturated fatty acid levels (linoleic acid)	3.000000e-21
GCST002448_6	Plasma omega-6 polyunsaturated fatty acid levels (adrenic acid)	4.000000e-140
GCST002449_6	Plasma omega-6 polyunsaturated fatty acid levels (arachidonic acid)	0.000000e+00
GCST002449_8	Plasma omega-6 polyunsaturated fatty acid levels (arachidonic acid)	7.000000e-147
GCST002450_8	Plasma omega-6 polyunsaturated fatty acid levels (gamma-linolenic acid)	2.000000e-72
GCST002454_8	Colorectal cancer	9.000000e-21
GCST002597_2	Laryngeal squamous cell carcinoma	1.000000e-20
GCST002712_12	Red blood cell fatty acid levels	2.000000e-12
GCST002712_2	Red blood cell fatty acid levels	8.000000e-90
GCST002712_3	Red blood cell fatty acid levels	1.000000e-09
GCST002712_4	Red blood cell fatty acid levels	3.000000e-305
GCST002712_7	Red blood cell fatty acid levels	3.000000e-19
GCST002712_8	Red blood cell fatty acid levels	2.000000e-10
GCST002712_9	Red blood cell fatty acid levels	6.000000e-43
GCST003818_34	Resting heart rate	2.000000e-30
GCST004132_88	Crohn’s disease	9.000000e-07
GCST004139_2	Bipolar disorder	1.000000e-10
GCST004139_22	Bipolar disorder	6.000000e-09
GCST005650_174	Serum metabolite ratios in chronic kidney disease	3.000000e-12
GCST005650_175	Serum metabolite ratios in chronic kidney disease	1.000000e-15

EFO canonical traits (33, from GWAS)

EFO ID	Trait name
EFO:0007760	eicosapentaenoic acid measurement
EFO:0006809	docosapentaenoic acid measurement
EFO:0007759	alpha-linolenic acid measurement
EFO:0004309	platelet count
EFO:0004471	insulin sensitivity measurement
EFO:0005680	omega-6 polyunsaturated fatty acid measurement
EFO:0006810	oleic acid measurement
EFO:0006808	arachidonic acid measurement
EFO:0006807	linoleic acid measurement
EFO:0006811	linolenic acid measurement
EFO:0007764	delta-5 desaturase measurement
EFO:0009131	response to polyunsaturated fatty acid supplementation
EFO:0009963	bipolar I disorder
EFO:0010364	lysophosphatidylcholine 20:5 measurement
EFO:0010365	lysophosphatidylcholine 22:6 measurement
EFO:0010422	triacylglycerol 54:4 measurement
EFO:0010363	lysophosphatidylcholine 20:4 measurement
EFO:0010373	phosphatidylcholine 32:1 measurement
EFO:0010341	cholesteryl ester 16:0 measurement
EFO:0010349	cholesteryl ester 20:5 measurement
EFO:0010370	lysophosphatidylethanolamine 20:4 measurement
EFO:0010414	triacylglycerol 52:2 measurement
EFO:0010348	cholesteryl ester 20:4 measurement
EFO:0010372	phosphatidylcholine 32:0 measurement
EFO:0010384	phosphatidylcholine 38:2 measurement
EFO:0010437	triacylglycerol 58:10 measurement
EFO:0010386	phosphatidylcholine 38:4 measurement
EFO:0010444	triacylglycerol 60:12 measurement
EFO:0004509	hemoglobin measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5027 (SINGLE PROTEIN)

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs174541	FADS1, FEN1, MIR611, TMEM258		0.00	0
rs4246215	FEN1		0.00	0
rs174538	FEN1, MIR611, TMEM258		0.00	0

Binding affinities (BindingDB)

1116 measured of 1241 human assays (1241 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-{2-Fluoro-4-[2-tetrahydro-2H- pyran-4-ylsulfonyl)-6- (trifluoromethyl)pyridin-3- yl]phenyl}pyrazin-2-amine	KI	0.3 nM	US-9745328: Flap modulators
6-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-benzylpyrimidin-4-amine	KI	0.4 nM	US-9073876: Flap modulators
5-[4-(2-cyclohexylsulfonyl-3-pyridinyl)-2-fluorophenyl]pyrazin-2-amine	KI	0.4 nM	US-9884878: FLAP modulators
2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]quinazolin-4-amine	KI	0.5 nM	US-9073876: Flap modulators
5-(4-{2-[(1,1-Dioxidotetrahydra-2H- thiopyran-4-yl)sulfonyl]-6- (trifluoromethyl)pyridin-3-yl}-2- fluorophenyl)pyrazin-2-amine	KI	0.5 nM	US-9745328: Flap modulators
5-[4-[2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]phenyl]-2-fluorophenyl]pyrazin-2-amine	KI	0.6 nM	US-9884878: FLAP modulators
5-[4-(2-cyclopentylsulfonyl-3-pyridinyl)-2-fluorophenyl]pyrazin-2-amine	KI	0.6 nM	US-9884878: FLAP modulators
2-[6-(2-aminopyrimidin-5-yl)-5-fluoro-3-pyridinyl]-N-tert-butylbenzenesulfonamide	KI	0.7 nM	US-9884878: FLAP modulators
5-[2-fluoro-4-(2-propan-2-ylsulfonyl-3-pyridinyl)phenyl]-1H-pyrrolo[2,3-b]pyridine	KI	0.7 nM	US-9884878: FLAP modulators
4-{[4’-(5-Aminopyrazin-2-yl)-3’- fluorobiphenyl-2-yl]oxy}benzoic acid	KI	0.7 nM	US-9745328: Flap modulators
4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-N,6-dimethylpyrimidin-2-amine	KI	0.9 nM	US-9073876: Flap modulators
5-[4-cyclobutyl-2-fluoro-3-(4-phenylpyrimidin-2-yl)oxyphenyl]pyrazin-2-amine	KI	1 nM	US-9073876: Flap modulators
5-[4-cyclobutyl-2-fluoro-3-(4-thiophen-2-ylpyrimidin-2-yl)oxyphenyl]pyrazin-2-amine	KI	1 nM	US-9073876: Flap modulators
6-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-methoxypyrimidin-4-amine	KI	1 nM	US-9073876: Flap modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-tert-butylbenzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-cyclohexylbenzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzenesulfonamide	KI	1 nM	US-9079866: Flap modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-[(1R)-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-phenylbenzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N,N-diethylbenzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
5-[4-[2-(3,3-difluoropiperidin-1-yl)sulfonylphenyl]-2-fluorophenyl]pyrazin-2-amine	KI	1 nM	US-9884878: FLAP modulators
1-[2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]phenyl]sulfonyl-4-(trifluoromethyl)piperidin-4-ol	KI	1 nM	US-9884878: FLAP modulators
[1-[2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]phenyl]sulfonylpiperidin-4-yl]methanol	KI	1 nM	US-9884878: FLAP modulators
2-[1-[2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]phenyl]sulfonylpiperidin-4-yl]ethanol	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-[(1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-[(1R)-2-hydroxy-1-phenylethyl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-[(1S,2S)-1-hydroxy-1-phenylpropan-2-yl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-(cyclopropylmethyl)benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-[(1R,2S)-2-(hydroxymethyl)cyclohexyl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
5-[2-fluoro-4-[2-(1,4,6,7-tetrahydropyrazolo[4,5-c]pyridin-5-ylsulfonyl)phenyl]phenyl]pyrazin-2-amine	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-(6-hydroxyhexyl)benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
N-(4-aminocyclohexyl)-2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-cyclohexyl-N-(2-hydroxyethyl)benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-cyclopropyl-N-(oxan-4-yl)benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-(2-hydroxyethyl)-N-propan-2-ylbenzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-(1,3-dihydroxy-2-methylpropan-2-yl)benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
tert-butyl N-[2-[[2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]phenyl]sulfonylamino]ethyl]carbamate	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-[6-(trifluoromethyl)-3-pyridinyl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
5-[2-fluoro-4-[2-[4-(1H-imidazol-5-yl)piperidin-1-yl]sulfonylphenyl]phenyl]pyrazin-2-amine	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-(3-methyloxetan-3-yl)benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-[(2S)-1-methoxypropan-2-yl]benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
4-[2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-5-(trifluoromethyl)phenyl]sulfonylpiperazin-2-one	KI	1 nM	US-9884878: FLAP modulators
2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide	KI	1 nM	US-9884878: FLAP modulators
5-[2-fluoro-4-[2-(4-methylpiperazin-1-yl)sulfonyl-4-(trifluoromethyl)phenyl]phenyl]pyrazin-2-amine	KI	1 nM	US-9884878: FLAP modulators
4-[2-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]phenyl]sulfanylpyrimidin-5-amine	KI	1 nM	US-9884878: FLAP modulators

ChEMBL bioactivities

1726 potent at pChembl≥5 of 1755 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL361962
10.96	IC50	0.011	nM	CHEMBL361546
10.92	IC50	0.012	nM	CHEMBL361011
10.85	IC50	0.014	nM	CHEMBL182687
10.85	IC50	0.014	nM	CHEMBL183792
10.74	IC50	0.018	nM	CHEMBL182519
10.64	IC50	0.023	nM	CHEMBL364591
10.60	IC50	0.025	nM	CHEMBL361350
10.55	IC50	0.028	nM	CHEMBL181709
10.51	IC50	0.031	nM	CHEMBL185325
10.47	IC50	0.034	nM	CHEMBL359747
10.46	IC50	0.035	nM	CHEMBL362205
10.42	IC50	0.038	nM	CHEMBL183133
10.37	IC50	0.043	nM	CHEMBL359533
10.14	IC50	0.072	nM	CHEMBL185322
10.12	IC50	0.076	nM	CHEMBL180566
10.10	IC50	0.079	nM	CHEMBL183852
10.09	IC50	0.082	nM	CHEMBL182381
9.87	IC50	0.135	nM	CHEMBL360615
9.85	IC50	0.143	nM	CHEMBL183539
9.84	IC50	0.146	nM	CHEMBL183062
9.64	IC50	0.23	nM	CHEMBL182974
9.54	IC50	0.285	nM	CHEMBL181766
9.52	Ki	0.3	nM	CHEMBL5775515
9.47	IC50	0.338	nM	CHEMBL181637
9.40	Ki	0.4	nM	CHEMBL3704300
9.40	Ki	0.4	nM	CHEMBL3700843
9.30	Ki	0.5	nM	CHEMBL3659304
9.30	Ki	0.5	nM	CHEMBL6013416
9.22	Ki	0.6	nM	CHEMBL3697283
9.22	Ki	0.6	nM	CHEMBL3700845
9.15	Ki	0.7	nM	CHEMBL3697342
9.15	Ki	0.7	nM	CHEMBL3700861
9.15	Ki	0.7	nM	CHEMBL5753490
9.10	Ki	0.8	nM	CHEMBL3704248
9.05	Ki	0.9	nM	CHEMBL3659301
9.00	Ki	1	nM	CHEMBL3704245
9.00	Ki	1	nM	CHEMBL3704248
9.00	Ki	1	nM	CHEMBL3704256
9.00	Ki	1	nM	CHEMBL3688400
9.00	Ki	1	nM	CHEMBL3688402
9.00	Ki	1	nM	CHEMBL3688404
9.00	Ki	1	nM	CHEMBL3688409
9.00	Ki	1	nM	CHEMBL3688415
9.00	Ki	1	nM	CHEMBL3688417
9.00	Ki	1	nM	CHEMBL3639872
9.00	Ki	1	nM	CHEMBL3688438
9.00	Ki	1	nM	CHEMBL3688441
9.00	Ki	1	nM	CHEMBL3688446
9.00	Ki	1	nM	CHEMBL3688458

PubChem BioAssay actives

72 with measured affinity, of 150 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
3-hydroxy-5,6,7,8-tetrahydro-1H-[1]benzothiolo[2,3-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
3-hydroxy-1-[(7-methoxy-1,3-benzodioxol-5-yl)methyl]-5-methylthieno[2,3-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
3-hydroxy-7-phenyl-1H-thieno[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
3-hydroxy-1H-[1]benzothiolo[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
1-benzyl-3-hydroxy-5-methylthieno[2,3-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
3-hydroxy-7-(4-phenylphenyl)-1H-furo[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
7-benzyl-3-hydroxy-1H-furo[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
N-[3-[3-[(3-hydroxy-2,4-dioxothieno[3,2-d]pyrimidin-1-yl)methyl]phenyl]phenyl]acetamide	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
1-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-3-hydroxythieno[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
4-[3-[(3-hydroxy-2,4-dioxothieno[3,2-d]pyrimidin-1-yl)methyl]phenyl]benzamide	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
7-(benzenesulfonyl)-3-hydroxy-1H-thieno[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
3-hydroxy-7-(3-methoxyphenyl)-1H-furo[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
3-hydroxy-1H-thieno[2,3-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
5-chloro-3-hydroxy-1H-quinazoline-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
3-hydroxy-5-methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
3-hydroxy-7-(4-methoxyphenyl)-1H-furo[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
3-hydroxy-1-(4-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	<0.0001	uM
3-hydroxy-6-phenyl-1H-thieno[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0001	uM
1-[(3-bromophenyl)methyl]-3-hydroxythieno[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0001	uM
6-tert-butyl-3-hydroxy-1H-thieno[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0001	uM
3-hydroxy-1H-quinazoline-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0001	uM
3-hydroxy-7-phenyl-1H-furo[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0001	uM
3-hydroxy-7-(4-methylphenyl)-1H-furo[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0001	uM
7-(4-bromophenyl)-3-hydroxy-1H-furo[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0001	uM
1-benzyl-3-hydroxythieno[2,3-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0002	uM
3-hydroxy-1H-[1]benzofuro[3,2-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0003	uM
3-hydroxy-1,5-dimethylthieno[2,3-d]pyrimidine-2,4-dione	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0003	uM
4-[3-[(3-hydroxy-7-methyl-2,4-dioxothieno[3,2-d]pyrimidin-1-yl)methyl]phenyl]benzamide	240866: Inhibitory concentration against the Flap endonuclease-1	ic50	0.0011	uM
3-hydroxy-1-[(4-methoxyphenyl)methyl]-4a,5,6,7,8,8a-hexahydroquinazoline-2,4-dione	1802030: Steady-State Kinetics from Article 10.1038/nchembio.2148: “Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site.”	ic50	0.0169	uM
1-(cyclopropylmethyl)-3-hydroxy-4aH-quinazolin-1-ium-2,4-dione	1802030: Steady-State Kinetics from Article 10.1038/nchembio.2148: “Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site.”	ic50	0.0300	uM
N-(3-hydroxy-2,4-dioxo-1H-quinazolin-8-yl)acetamide	1247799: Inhibition of FEN1 (unknown origin)	ic50	0.0380	uM
4-[2-chloro-5-(4-methoxyphenyl)phenyl]-2,4-dioxobutanoic acid	240664: Concentration required for 50% inhibition of Flap endonuclease-1	ic50	0.1900	uM
7-anilino-3-hydroxy-1H-quinazoline-2,4-dione	1247799: Inhibition of FEN1 (unknown origin)	ic50	0.2300	uM
2-hydroxybenzo[de]isoquinoline-1,3-dione	1247799: Inhibition of FEN1 (unknown origin)	ic50	0.3000	uM
4-(2-chloro-5-phenylphenyl)-2,4-dioxobutanoic acid	240664: Concentration required for 50% inhibition of Flap endonuclease-1	ic50	0.3300	uM
4-[2-chloro-4-(4-chlorophenyl)phenyl]-2,4-dioxobutanoic acid	240664: Concentration required for 50% inhibition of Flap endonuclease-1	ic50	0.4100	uM
2,4-dioxo-4-[5-[4-(trifluoromethoxy)phenyl]thiophen-2-yl]butanoic acid	240664: Concentration required for 50% inhibition of Flap endonuclease-1	ic50	0.4400	uM
4-[5-(4-chloro-3-fluorophenyl)thiophen-2-yl]-2,4-dioxobutanoic acid	240664: Concentration required for 50% inhibition of Flap endonuclease-1	ic50	0.5700	uM
3-hydroxy-6-phenyl-1H-pyrimidine-2,4-dione	1247799: Inhibition of FEN1 (unknown origin)	ic50	0.6300	uM
6-chloro-2-hydroxybenzo[de]isoquinoline-1,3-dione	1247799: Inhibition of FEN1 (unknown origin)	ic50	0.7000	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148381: Binding affinity to human FEN1 incubated for 45 mins by Kinobead based pull down assay	kd	1.0247	uM
3-hydroxy-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione	1247799: Inhibition of FEN1 (unknown origin)	ic50	1.1000	uM
N-butan-2-yl-5-hydroxy-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247799: Inhibition of FEN1 (unknown origin)	ic50	1.3000	uM
4-[3-(4-methoxyphenyl)phenyl]-2,4-dioxobutanoic acid	240664: Concentration required for 50% inhibition of Flap endonuclease-1	ic50	1.3600	uM
2,4-dioxo-4-[5-(trifluoromethyl)thiophen-2-yl]butanoic acid	240664: Concentration required for 50% inhibition of Flap endonuclease-1	ic50	1.5200	uM
2,4-dioxo-4-(5-phenylfuran-2-yl)butanoic acid	240664: Concentration required for 50% inhibition of Flap endonuclease-1	ic50	1.6600	uM
2,4-dioxo-4-(4-phenoxyphenyl)butanoic acid	240664: Concentration required for 50% inhibition of Flap endonuclease-1	ic50	1.7500	uM
4-(2,5-dichlorophenyl)-2,4-dioxobutanoic acid	240664: Concentration required for 50% inhibition of Flap endonuclease-1	ic50	1.8200	uM
N-(3-hydroxy-2,4-dioxo-1H-quinazolin-6-yl)acetamide	1247799: Inhibition of FEN1 (unknown origin)	ic50	2.0000	uM
N-[(4-fluorophenyl)methyl]-5-hydroxy-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247799: Inhibition of FEN1 (unknown origin)	ic50	2.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases reaction, affects expression, decreases expression, increases expression	7
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
Cisplatin	decreases expression, decreases reaction, increases expression, affects response to substance, decreases response to substance	4
Acetaminophen	increases expression, decreases reaction	3
Tretinoin	decreases expression	3
Cyclosporine	increases expression, decreases expression	3
4-biphenylamine	decreases expression, decreases reaction	2
cobaltous chloride	decreases expression	2
Benzo(a)pyrene	increases expression, decreases expression	2
Cannabidiol	decreases expression	2
Estradiol	increases expression	2
Fluorouracil	affects response to substance, increases expression	2
Hydrogen Peroxide	decreases expression	2
Mustard Gas	decreases expression	2
Tetrachlorodibenzodioxin	decreases expression, affects expression	2
Aflatoxin B1	affects expression, increases expression	2
tert-Butylhydroperoxide	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
afuresertib	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
pradimicin-IRD	decreases expression, affects expression, affects response to substance	1
urushiol	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
myristicin	decreases expression	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
sodium arsenate	decreases expression	1
titanium dioxide	affects binding, decreases expression	1
N(4)-hydroxycytidine	increases expression	1

ChEMBL screening assays

15 unique, capped per target: 12 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1613922	Functional	PUBCHEM_BIOASSAY: qHTS Validation Assay for the Inhibitors of Human Flap endonuclease 1 (FEN1). (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL3619485	Binding	Inhibition of FEN1 (unknown origin)	N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8FZ	Abcam HCT 116 FEN1 KO	Cancer cell line	Male
CVCL_B8VT	Abcam MCF-7 FEN1 KO	Cancer cell line	Female
CVCL_B9I6	Abcam A-549 FEN1 KO	Cancer cell line	Male
CVCL_D7PT	Ubigene A-549 FEN1 KO	Cancer cell line	Male
CVCL_KT57	HeLa SilenciX FEN1	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT04308603	Not specified	COMPLETED	Multicentric Prospective Study to Screen Inborn Errors of Metabolism in Non-immune Hydrops (NIH) Fetalis by Massively Parallel Sequencing
NCT05528796	Not specified	ENROLLING_BY_INVITATION	Uncovering the Etiologies of Non-immune Hydrops Fetalis
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives