WRN

Summary

WRN (WRN RecQ like helicase, HGNC:12791) is a protein-coding gene on chromosome 8p12, encoding Bifunctional 3’-5’ exonuclease/ATP-dependent helicase WRN (Q14191). Multifunctional enzyme that has magnesium and ATP-dependent 3’-5’ DNA-helicase activity on partially duplex substrates.

This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3’ to 5’ exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by accelerated aging and an elevated risk for certain cancers.

Source: NCBI Gene 7486 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Werner syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 3,819 total — 252 pathogenic, 156 likely-pathogenic
• Phenotypes (HPO): 84
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000553

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12791
Approved symbol	WRN
Name	WRN RecQ like helicase
Location	8p12
Locus type	gene with protein product
Status	Approved
Aliases	RECQL2, RECQ3
Ensembl gene	ENSG00000165392
Ensembl biotype	protein_coding
OMIM	604611
Entrez	7486

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000298139, ENST00000520169, ENST00000521620, ENST00000650667, ENST00000651642, ENST00000651946, ENST00000860283, ENST00000860284, ENST00000860285, ENST00000860286, ENST00000928033, ENST00000928034, ENST00000966175, ENST00000966176

RefSeq mRNA: 1 — MANE Select: NM_000553 NM_000553

CCDS: CCDS6082

Canonical transcript exons

ENST00000298139 — 35 exons

Exon	Start	End
ENSE00001092693	31058372	31058543
ENSE00001092694	31059153	31059265
ENSE00001092701	31090465	31090532
ENSE00001092708	31064915	31065063
ENSE00001092711	31076173	31076287
ENSE00001092732	31068258	31068327
ENSE00001092733	31064289	31064434
ENSE00001092739	31080867	31081296
ENSE00001092740	31087776	31087920
ENSE00001158180	31067033	31067182
ENSE00001158217	31033810	31033973
ENSE00001620781	31085166	31085246
ENSE00001687979	31083699	31083779
ENSE00003473364	31141430	31141600
ENSE00003474151	31100849	31100955
ENSE00003487006	31143550	31143623
ENSE00003491959	31090834	31090942
ENSE00003524124	31142626	31142701
ENSE00003531902	31096768	31096850
ENSE00003544032	31141681	31141775
ENSE00003552139	31124522	31124623
ENSE00003570260	31150341	31150455
ENSE00003573191	31116354	31116528
ENSE00003577892	31147053	31147128
ENSE00003579794	31120243	31120424
ENSE00003589497	31157368	31157530
ENSE00003597102	31124908	31125000
ENSE00003643889	31088890	31088965
ENSE00003645882	31111615	31111799
ENSE00003653441	31147364	31147476
ENSE00003657184	31154624	31154755
ENSE00003670203	31091830	31091898
ENSE00003674305	31167022	31167230
ENSE00003693067	31132365	31132506
ENSE00003850946	31172995	31176138

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 93.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.0836 / max 292.7918, expressed in 1790 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88328	17.2638	1788
88329	0.7793	437
205149	0.0405	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	93.90	gold quality
sperm	CL:0000019	92.94	gold quality
male germ cell	CL:0000015	89.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.04	gold quality
adrenal tissue	UBERON:0018303	86.52	gold quality
colonic epithelium	UBERON:0000397	86.42	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.48	gold quality
mucosa of stomach	UBERON:0001199	85.44	gold quality
secondary oocyte	CL:0000655	85.28	gold quality
body of uterus	UBERON:0009853	84.05	gold quality
sural nerve	UBERON:0015488	84.00	gold quality
ventricular zone	UBERON:0003053	83.86	gold quality
skin of abdomen	UBERON:0001416	83.66	gold quality
body of pancreas	UBERON:0001150	83.58	gold quality
right testis	UBERON:0004534	83.36	gold quality
skin of leg	UBERON:0001511	83.24	gold quality
left testis	UBERON:0004533	82.95	gold quality
testis	UBERON:0000473	82.88	gold quality
left ovary	UBERON:0002119	82.51	gold quality
right ovary	UBERON:0002118	82.18	gold quality
tendon	UBERON:0000043	82.06	gold quality
left uterine tube	UBERON:0001303	81.96	gold quality
tibial nerve	UBERON:0001323	81.93	gold quality
cartilage tissue	UBERON:0002418	81.84	gold quality
ovary	UBERON:0000992	81.81	gold quality
zone of skin	UBERON:0000014	81.58	gold quality
pancreas	UBERON:0001264	81.31	gold quality
ectocervix	UBERON:0012249	81.25	gold quality
bone marrow	UBERON:0002371	81.21	gold quality
popliteal artery	UBERON:0002250	81.11	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, RB1, SIRT1, SP1, TP53

miRNA regulators (miRDB)

44 targeting WRN, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-136-5P	99.50	67.26	1153
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-892C-5P	99.16	70.56	2116

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• A functional interaction of Ku with Werner exonuclease facilitates digestion of DNA containing 8-oxoadenine and 8-oxoguanine modifications. (PMID:11328876)
• Lack of WRN results in extensive deletion at nonhomologous joining ends. (PMID:11809708)
• The active form of this minimal exonuclease fragment of human WRN appears to be a hexamer. (PMID:11863428)
• Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins (PMID:11919194)
• WRN helicase accelerates the transcription of ribosomal RNA as a component of an RNA polymerase I-associated complex (PMID:11971179)
• Distinct proteins encoded by alternative transcripts of the PURG gene, located contrapodal to WRN on chromosome 8, determined by differential termination/polyadenylation. (PMID:12034829)
• recombinant p53 binds to BLM and WRN helicases and attenuates their ability to unwind synthetic Holliday junctions in vitro (PMID:12080066)
• Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus (PMID:12177300)
• binding by and stimulation of by telomere-binding proteing TRF2 (PMID:12181313)
• physiological role for the WRN RecQ helicase protein in RAD51-dependent homologous recombination (PMID:12242278)
• A nucleolar targeting sequence in this protein resides within amino acid residues 949-1092. (PMID:12244128)
• interaction of the WRN gene product with human 5’ flap endonuclease/5’-3’ exonuclease (FEN-1) (PMID:12356323)
• DNA damage-induced translocation is regulated by acetylation (PMID:12384494)
• WRN is phosphorylated through an ATR/ATM dependent pathway in response to replication blockage, WRN phosphorylation is not essential for its subnuclear relocalization after replication arrest. WRN and ATR colocalize after replication fork arrest (PMID:12629512)
• PCNA binds to two distinct functional sites on WRN (PMID:12633936)
• stimulates DNA polymerase beta strand displacement synthesis via its helicase activity (PMID:12665521)
• The functional interaction between WRN and EXO-1 is mediated by a protein domain of WRN which interacts with flap endonuclease 1. (PMID:12704184)
• coordinated WRN and RAD52 activities are involved in replication fork rescue after DNA damage (PMID:12750383)
• WRN plays a role in the activation of G2 decatenation checkpoint. The abortive function of this pathway itself does not appear sufficient to cause genomic instability. It predisposes to genomic instability & apoptosis in the absence of “caretaker” genes. (PMID:12810661)
• results demonstrate that MYC directly stimulates transcription of WRN; propose that WRN up-regulation by MYC may promote MYC-driven tumorigenesis by preventing cellular senescence (PMID:12842909)
• The balanced exonuclease and helicase activities of Werner protein are required for optimal homologous recombination. Moreover, Werner protein appears to play a structural role, independent of its enzymatic activities. (PMID:12934712)
• valosin /WRNp interaction plays an important role in Werner syndrome biology (PMID:12937274)
• we have identified a direct binding between WRN and c-Abl in vitro via the N-terminal and central regions of WRN and the Src homology domain 3 of c-Abl. These findings suggest a novel signaling pathway (PMID:12944467)
• Human replication protein A, by engaging in both protein-protein and protein-DNA interactions, facilitates unwinding catalyzed by WRN helicase during DNA synthetic processes. (PMID:14499497)
• Werner syndrome protein contains three structure-specific DNA binding domains (PMID:14534320)
• interaction of ADPRT and WRN resulting in ADP-ribosylation of the WRN protein; results imply that WRN is involved in DNA replication and in DNA repair (PMID:14596914)
• the WRN/PARP-1 complex plays a key role in the cellular response to oxidative stress and alkylating agents, suggesting a role for these proteins in the base excision DNA repair pathway (PMID:14612404)
• WRN effectively stimulates FEN-1 cleavage of branch-migrating double-flap structures that are the physiological substrates of FEN-1 during replication. (PMID:14657243)
• (ADP-ribosyl)ation of Ku70/80 reduces the ability of this factor to stimulate WRN exonuclease, suggesting that covalent modification of Ku70/80 by PARP-1 may play a role in the regulation of the exonucleolytic activity of WRN. (PMID:14734561)
• WRN associates with the Mre11 complex via binding to Nbs1 in vitro and in vivo. (PMID:15026416)
• results suggest that VCP plays a mechanistic role in releasing WRNp from the nucleolus (PMID:15037256)
• WRN missense mutations or polymorphisms could promote genetic instability and cancer in the general population by selectively interfering with recombination in somatic cells (PMID:15084309)
• WRN and TP53 perform different functions in a shared DNA damage response pathway. (PMID:15149862)
• kinetic analysis of helicase and exonuclease activities of WRN (PMID:15187093)
• C/R polymorphism of WRN does not affect enzyme function or localization and does not influence the incidence of the coronary artery disease (PMID:15246744)
• a functional interaction between Werner syndrome protein and two factors that bind to DNA breaks, Ku and poly(ADP-ribose) polymerase 1–REVIEW (PMID:15336909)
• WRN helicase activity is regulated in human base excision repair (PMID:15385537)
• These results suggest a functional relationship between WRN and the MRE11 complex in response to replication fork arrest, disclosing a common action of WRN and the MRE11 complex in the pathway(s) preserving genome stability during DNA replication. (PMID:15467456)
• R834C is a missense amino acid polymorphism in WRN that nearly abolishes enzymatic activity while leaving expression largely unaffected (PMID:15489508)
• cells lacking WRN exhibit deletion of telomeres from single sister chromatids;it is proposed that WRN is necessary for efficient replication of G-rich telomeric DNA, preventing telomere dysfunction and consequent genomic instability (PMID:15591207)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	wrn	ENSDARG00000098211
mus_musculus	Wrn	ENSMUSG00000031583
rattus_norvegicus	Wrn	ENSRNOG00000015440
caenorhabditis_elegans		WBGENE00006944

Paralogs (4): RECQL (ENSG00000004700), RECQL5 (ENSG00000108469), RECQL4 (ENSG00000160957), BLM (ENSG00000197299)

Protein

Protein identifiers

Bifunctional 3’-5’ exonuclease/ATP-dependent helicase WRN — Q14191 (reviewed: Q14191)

Alternative names: DNA helicase, RecQ-like type 3, RecQ protein-like 2, Werner syndrome protein

All UniProt accessions (3): A0A494C0M3, A0A494C0Y6, Q14191

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional enzyme that has magnesium and ATP-dependent 3’-5’ DNA-helicase activity on partially duplex substrates. Also has 3’->5’ exonuclease activity towards double-stranded (ds)DNA with a 5’-overhang. Has no nuclease activity towards single-stranded (ss)DNA or blunt-ended dsDNA. Helicase activity is most efficient with (d)ATP, but (d)CTP will substitute with reduced efficiency; strand displacement is enhanced by single-strand binding-protein (heterotrimeric replication protein A complex, RPA1, RPA2, RPA3). Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A. Plays a role in double-strand break repair after gamma-irradiation. Unwinds some G-quadruplex DNA (d(CGG)n tracts); unwinding seems to occur in both 5’-3’ and 3’-5’ direction and requires a short single-stranded tail. d(CGG)n tracts have a propensity to assemble into tetraplex structures; other G-rich substrates from a telomeric or IgG switch sequence are not unwound. Depletion leads to chromosomal breaks and genome instability.

Subunit / interactions. Monomer, and homooligomer. May exist as homodimer, homotrimer, homotetramer and/or homohexamer. Homotetramer, or homohexamer, when bound to DNA. Interacts via its N-terminal domain with WRNIP1. Interacts with EXO1, PCNA and SUPV3L1. Interacts with PML (isoform PML-4). Interacts (via KBM motif) with XRCC5 and XRCC6; promoting recruitment to DNA damage sites. Interacts with RECQL5; this interaction stimulates WRN helicase activity on DNA fork duplexes.

Subcellular location. Nucleus. Nucleolus. Nucleoplasm. Chromosome.

Post-translational modifications. Phosphorylated by PRKDC.

Disease relevance. Werner syndrome (WRN) [MIM:277700] A rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus, ocular cataracts and osteoporosis. The major cause of death, at a median age of 47, is myocardial infarction. The disease is caused by variants affecting the gene represented in this entry. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. The disease may be caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 magnesium or manganese ions in the exonuclease domain; has high exonuclease activity with both ions in vitro. Unwinding of G-quadruplex DNA requires Mg(2+). Binds a Zn(2+) ion in the helicase domain.

Domain organisation. The KBM 2 (Ku-binding motif 2) and XLM (XLF-like motif) mediate cooperative interaction with XRCC5/Ku80 and XRCC6/Ku70 and recruitment to DNA damage sites. The isolated helicase core (residues 517-1093) interacts weakly with the HDRC domain in vitro.

Similarity. Belongs to the helicase family. RecQ subfamily.

RefSeq proteins (1): NP_000544* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR002121	HRDC_dom	Domain
IPR002562	3’-5’_exonuclease_dom	Domain
IPR004589	DNA_helicase_ATP-dep_RecQ	Family
IPR010997	HRDC-like_sf	Homologous_superfamily
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR014001	Helicase_ATP-bd	Domain
IPR018982	RQC_domain	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR029491	Helicase_HTH	Domain
IPR032284	RecQ_Zn-bd	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR036397	RNaseH_sf	Homologous_superfamily
IPR044876	HRDC_dom_sf	Homologous_superfamily

Pfam: PF00270, PF00271, PF00570, PF01612, PF09382, PF14493, PF16124

Enzyme classification (BRENDA):

• EC 3.6.4.12 — DNA helicase (BRENDA: 0 organisms, 0 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (165 total): helix 46, strand 30, sequence variant 27, binding site 13, mutagenesis site 13, modified residue 8, turn 6, region of interest 4, short sequence motif 4, domain 4, cross-link 3, repeat 2, site 2, initiator methionine 1, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

51 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
10AK	X-RAY DIFFRACTION	1.37
7GQU	X-RAY DIFFRACTION	1.54
9OWB	X-RAY DIFFRACTION	1.56
7GQS	X-RAY DIFFRACTION	1.57
9MJU	X-RAY DIFFRACTION	1.58
7XUT	X-RAY DIFFRACTION	1.6
8PFP	X-RAY DIFFRACTION	1.6
9MJY	X-RAY DIFFRACTION	1.63
9OG8	X-RAY DIFFRACTION	1.66
9OWC	X-RAY DIFFRACTION	1.67
9MJZ	X-RAY DIFFRACTION	1.7
9MJT	X-RAY DIFFRACTION	1.73
9MJX	X-RAY DIFFRACTION	1.73
8PFL	X-RAY DIFFRACTION	1.8
9MJS	X-RAY DIFFRACTION	1.84
8YLE	X-RAY DIFFRACTION	1.86
9MK0	X-RAY DIFFRACTION	1.89
3AAF	X-RAY DIFFRACTION	1.9
8PFO	X-RAY DIFFRACTION	1.9
9S17	X-RAY DIFFRACTION	1.91
6TYV	X-RAY DIFFRACTION	1.93
9S1A	X-RAY DIFFRACTION	1.96
9OWD	X-RAY DIFFRACTION	1.96
9OWA	X-RAY DIFFRACTION	1.98
9S18	X-RAY DIFFRACTION	2
2E1F	X-RAY DIFFRACTION	2
2FBY	X-RAY DIFFRACTION	2
2FC0	X-RAY DIFFRACTION	2
9MJW	X-RAY DIFFRACTION	2
2FBT	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14191-F1	68.75	0.28

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 (2): 145 (interaction with dna); 1037 (interaction with dna)

Ligand- & substrate-binding residues (13): 82; 82; 84; 216; 546; 548; 550; 553; 574; 908; 935; 936 …

Post-translational modifications (11): 2, 426, 440, 453, 467, 478, 1133, 1400, 154, 241, 252

Mutagenesis-validated functional residues (13):

Position	Phenotype
18	abolished interaction with xrcc5 and xrcc6.
84	abolishes exonuclease activity. restores chromosome stability in depletion experiments.
88	no effect on exonuclease activity.
145	reduces exonuclease activity.
212	strongly reduces exonuclease activity.
577	loss of helicase activity, loss of dna-dependent atpase activity. does not restore chromosome stability in depletion exp
669	does not restore chromosome stability in depletion experiments.
987	reduces affinity for dna about 8-fold. loss of dna binding; when associated with a-993.
989	reduces affinity for dna about 4-fold.
993	reduces affinity for dna about 20-fold. loss of dna binding; when associated with a-987.
993	loss of dna binding.
1037	reduces affinity for dna about 8-fold.
1038	reduces affinity for dna about 4-fold.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-174414	Processive synthesis on the C-strand of the telomere
R-HSA-174437	Removal of the Flap Intermediate from the C-strand
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-5685938	HDR through Single Strand Annealing (SSA)
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693554	Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)
R-HSA-5693568	Resolution of D-loop Structures through Holliday Junction Intermediates
R-HSA-5693579	Homologous DNA Pairing and Strand Exchange
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-9701192	Defective homologous recombination repair (HRR) due to BRCA1 loss of function
R-HSA-9704331	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function
R-HSA-9704646	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function
R-HSA-9709570	Impaired BRCA2 binding to RAD51
R-HSA-9709603	Impaired BRCA2 binding to PALB2

MSigDB gene sets: 437 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_CHROMOSOME_ORGANIZATION, GOBP_RESPONSE_TO_UV_C, CREL_01, GOBP_RESPONSE_TO_IONIZING_RADIATION, PID_TELOMERASE_PATHWAY, GOBP_CELL_CYCLE_DNA_REPLICATION, GOMF_NUCLEASE_ACTIVITY, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_GROWTH, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_TELOMERE_ORGANIZATION, GOBP_CELLULAR_RESPONSE_TO_GAMMA_RADIATION, GOBP_CELLULAR_SENESCENCE, KAUFFMANN_DNA_REPAIR_GENES

GO Biological Process (28): telomere maintenance (GO:0000723), double-strand break repair via homologous recombination (GO:0000724), DNA synthesis involved in DNA repair (GO:0000731), DNA metabolic process (GO:0006259), DNA replication (GO:0006260), base-excision repair (GO:0006284), mismatch repair (GO:0006298), double-strand break repair (GO:0006302), DNA damage response (GO:0006974), response to oxidative stress (GO:0006979), determination of adult lifespan (GO:0008340), cellular response to starvation (GO:0009267), response to UV-C (GO:0010225), replication fork processing (GO:0031297), telomere maintenance via semi-conservative replication (GO:0032201), DNA geometric change (GO:0032392), regulation of growth rate (GO:0040009), positive regulation of hydrolase activity (GO:0051345), telomeric D-loop disassembly (GO:0061820), cellular response to gamma radiation (GO:0071480), cellular senescence (GO:0090398), replicative senescence (GO:0090399), t-circle formation (GO:0090656), positive regulation of strand invasion (GO:0098530), protein localization to nucleolus (GO:1902570), nucleobase-containing compound metabolic process (GO:0006139), DNA repair (GO:0006281), DNA recombination (GO:0006310)

GO Molecular Function (32): magnesium ion binding (GO:0000287), four-way junction DNA binding (GO:0000400), Y-form DNA binding (GO:0000403), bubble DNA binding (GO:0000405), DNA binding (GO:0003677), DNA helicase activity (GO:0003678), exonuclease activity (GO:0004527), ATP binding (GO:0005524), 3’-5’ exonuclease activity (GO:0008408), four-way junction helicase activity (GO:0009378), ATP hydrolysis activity (GO:0016887), manganese ion binding (GO:0030145), MutLalpha complex binding (GO:0032405), protein homodimerization activity (GO:0042803), 3’-5’ DNA helicase activity (GO:0043138), protein-containing complex binding (GO:0044877), G-quadruplex DNA binding (GO:0051880), forked DNA-dependent helicase activity (GO:0061749), telomeric D-loop binding (GO:0061821), telomeric G-quadruplex DNA binding (GO:0061849), 3’-flap-structured DNA binding (GO:0070337), 8-hydroxy-2’-deoxyguanosine DNA binding (GO:1905773), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), catalytic activity (GO:0003824), helicase activity (GO:0004386), nuclease activity (GO:0004518), protein binding (GO:0005515), hydrolase activity (GO:0016787), isomerase activity (GO:0016853), metal ion binding (GO:0046872), catalytic activity, acting on DNA (GO:0140097)

GO Cellular Component (9): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork (GO:0005657), chromosome (GO:0005694), nucleolus (GO:0005730), cytoplasm (GO:0005737), centrosome (GO:0005813), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	3
Resolution of D-Loop Structures	2
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	2
Telomere C-strand (Lagging Strand) Synthesis	1
Processive synthesis on the C-strand of the telomere	1
SUMO E3 ligases SUMOylate target proteins	1
HDR through Homologous Recombination (HRR)	1
Homologous DNA Pairing and Strand Exchange	1
Regulation of TP53 Activity	1
G2/M Checkpoints	1
Diseases of DNA Double-Strand Break Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA repair	4
DNA secondary structure binding	3
DNA helicase activity	3
cellular anatomical structure	3
DNA metabolic process	2
DNA biosynthetic process	2
cellular response to stress	2
nuclear lumen	2
intracellular membraneless organelle	2
telomere organization	1
recombinational repair	1
double-strand break repair	1
nucleic acid metabolic process	1
response to stress	1
multicellular organismal process	1
cellular response to nutrient levels	1
response to starvation	1
response to UV	1
DNA-templated DNA replication maintenance of fidelity	1
telomere maintenance	1
cell cycle process	1
nuclear DNA replication	1
DNA conformation change	1
regulation of growth	1
hydrolase activity	1
positive regulation of catalytic activity	1
regulation of hydrolase activity	1
telomeric loop disassembly	1
response to gamma radiation	1
cellular response to ionizing radiation	1
metal ion binding	1
nucleic acid binding	1
helicase activity	1
ATP-dependent activity, acting on DNA	1
nuclease activity	1
hydrolase activity, acting on ester bonds	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
exonuclease activity	1
ribonucleoside triphosphate phosphatase activity	1

Protein interactions and networks

STRING

2855 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WRN	WRNIP1	Q96S55	996
WRN	DNA2	P51530	994
WRN	FEN1	P39748	991
WRN	EXO1	Q9UQ84	986
WRN	XRCC6	P12956	982
WRN	RAD52	P43351	969
WRN	PRKDC	P78527	968
WRN	RAD51	Q06609	966
WRN	XRCC5	P13010	953
WRN	TERF1	P54274	944
WRN	TOP3A	Q13472	928
WRN	RMI1	Q9H9A7	910
WRN	SIRT6	Q8N6T7	895
WRN	BRCA1	P38398	892
WRN	ATM	Q13315	874

IntAct

157 interactions, top by confidence:

A	B	Type	Score
XRCC6	XRCC5	psi-mi:“MI:0914”(association)	0.970
XRCC5	XRCC6	psi-mi:“MI:0217”(phosphorylation reaction)	0.970
RPA2	RPA1	psi-mi:“MI:0914”(association)	0.960
RPA1	RPA2	psi-mi:“MI:0914”(association)	0.960
SUV39H1	CBX5	psi-mi:“MI:0914”(association)	0.950
RPA3	RPA2	psi-mi:“MI:0914”(association)	0.930
XRCC6	WRN	psi-mi:“MI:0915”(physical association)	0.930
WRN	XRCC6	psi-mi:“MI:0914”(association)	0.930
WRN	XRCC6	psi-mi:“MI:0217”(phosphorylation reaction)	0.930
XRCC5	PARP1	psi-mi:“MI:0915”(physical association)	0.880
PARP1	XRCC6	psi-mi:“MI:0914”(association)	0.850
PARP1	XRCC6	psi-mi:“MI:0915”(physical association)	0.850
WRN	RPA1	psi-mi:“MI:0915”(physical association)	0.820
RPA1	WRN	psi-mi:“MI:0915”(physical association)	0.820
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

BioGRID (246): WRN (Biochemical Activity), SIRT1 (Reconstituted Complex), SIRT1 (Affinity Capture-Western), WRN (Affinity Capture-Western), CREBBP (Affinity Capture-Western), WRN (Reconstituted Complex), WRN (Affinity Capture-MS), WRN (Affinity Capture-MS), WRN (Affinity Capture-MS), WRN (Synthetic Growth Defect), WRN (Synthetic Growth Defect), WRN (Affinity Capture-MS), WRN (Affinity Capture-MS), WRN (Affinity Capture-MS), WRN (Reconstituted Complex)

ESM2 similar proteins: A0A1P8ASY1, A2Q1V6, A2XYY8, A2YP56, A2ZM73, A3BMN9, A3KPF2, A4PBL4, A6ZRL7, C0SUU8, C0SV12, F4HPZ9, F4I240, F4I6G4, F4I9Q5, F4JUI9, O64752, O65628, O80831, P0CB22, P29375, P53867, Q08A71, Q0WVD6, Q14191, Q1EHT7, Q2QMW0, Q3UXZ9, Q64MA3, Q6K431, Q7XKC0, Q84MA1, Q84RR2, Q8GUI6, Q8L7W2, Q8LMR2, Q8VXV7, Q8VYB7, Q8VYB9, Q9C5X4

Diamond homologs: A2XVF7, A3AVH5, A4RK80, A8WK63, D4ACP5, G2TRN7, O09053, O18017, O34748, O88700, O93530, O94761, O94762, P0CQ88, P0CQ89, P15043, P35187, P40724, P46063, P50729, P54132, P71359, P73421, Q09811, Q0WVW7, Q14191, Q19546, Q5RF63, Q5UPX0, Q6AYJ1, Q75NR7, Q7RZH4, Q8L840, Q8VID5, Q9CL21, Q9DEY9, Q9FT70, Q9FT72, Q9FT73, Q9FT74

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
PRKDC	up-regulates	WRN	phosphorylation
WRN	“up-regulates activity”	DNA_repair
ATR	“down-regulates quantity by destabilization”	WRN	phosphorylation
ATR	“down-regulates quantity”	WRN	phosphorylation
ABL1	up-regulates	WRN	phosphorylation
ATM	unknown	WRN	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 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
Removal of the Flap Intermediate from the C-strand	6	55.2×	4e-07
Translesion Synthesis by POLH	5	43.5×	1e-05
Gap-filling DNA repair synthesis and ligation in GG-NER	5	31.8×	2e-05
HDR through Single Strand Annealing (SSA)	7	29.7×	9e-07
Recognition of DNA damage by PCNA-containing replication complex	5	27.6×	4e-05
Impaired BRCA2 binding to RAD51	6	26.8×	1e-05
Presynaptic phase of homologous DNA pairing and strand exchange	6	23.6×	2e-05
Negative epigenetic regulation of rRNA expression	6	22.6×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
base-excision repair	6	33.8×	2e-06
nucleotide-excision repair	6	27.7×	6e-06
telomere maintenance	8	25.8×	1e-07
cellular response to ionizing radiation	5	24.8×	1e-04
double-strand break repair	10	24.5×	4e-09
DNA recombination	6	24.4×	1e-05
double-strand break repair via homologous recombination	12	22.6×	1e-10
heterochromatin formation	7	21.5×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

3819 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	252
Likely pathogenic	156
Uncertain significance	1905
Likely benign	1196
Benign	116

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068480	NM_000553.6(WRN):c.655-1G>A	Pathogenic
1068691	NM_000553.6(WRN):c.754A>T (p.Lys252Ter)	Pathogenic
1069486	NM_000553.6(WRN):c.1228C>T (p.Gln410Ter)	Pathogenic
1070555	NM_000553.6(WRN):c.2894dup (p.Leu966fs)	Pathogenic
1070821	NM_000553.6(WRN):c.1472dup (p.His491fs)	Pathogenic
1070898	NM_000553.6(WRN):c.15dup (p.Leu6fs)	Pathogenic
1071111	NM_000553.6(WRN):c.3310-1_3369dup	Pathogenic
1071113	NM_000553.6(WRN):c.1726G>T (p.Gly576Ter)	Pathogenic
1071703	NC_000008.10:g.(?30998936)(31015056_?)del	Pathogenic
1071704	NC_000008.10:g.(?31007847)(31015056_?)del	Pathogenic
1071705	NC_000008.10:g.(?_31014911)_31015491del	Pathogenic
1071823	NM_000553.6(WRN):c.2177_2178dup (p.Cys727fs)	Pathogenic
1071984	NM_000553.6(WRN):c.1674_1677del (p.His558fs)	Pathogenic
1072949	NM_000553.6(WRN):c.1252del (p.Ala418fs)	Pathogenic
1073048	NM_000553.6(WRN):c.3851_3982+449del	Pathogenic
1073193	NM_000553.6(WRN):c.2884C>T (p.Gln962Ter)	Pathogenic
1074018	NM_000553.6(WRN):c.928_929dup (p.Pro311fs)	Pathogenic
1074089	NM_000553.6(WRN):c.3288del (p.Glu1097fs)	Pathogenic
1074587	NM_000553.6(WRN):c.724G>T (p.Glu242Ter)	Pathogenic
1075005	NM_000553.6(WRN):c.2551G>T (p.Glu851Ter)	Pathogenic
1075177	NM_000553.6(WRN):c.2031del (p.His678fs)	Pathogenic
1075339	NM_000553.6(WRN):c.1009_1013del (p.Glu337fs)	Pathogenic
1075594	NM_000553.6(WRN):c.1301del (p.Thr434fs)	Pathogenic
1075888	NM_000553.6(WRN):c.2106dup (p.Thr703fs)	Pathogenic
1076184	NM_000553.6(WRN):c.2820del (p.Arg940fs)	Pathogenic
1076329	NM_000553.6(WRN):c.1920C>G (p.Tyr640Ter)	Pathogenic
1076472	NM_000553.6(WRN):c.3769C>T (p.Gln1257Ter)	Pathogenic
1076649	NM_000553.6(WRN):c.2855C>G (p.Ser952Ter)	Pathogenic
1319395	NM_000553.6(WRN):c.2704del (p.Tyr902fs)	Pathogenic
1323773	NM_000553.6(WRN):c.3244_3245del (p.Val1082fs)	Pathogenic

SpliceAI

6270 predictions. Top by Δscore:

Variant	Effect	Δscore
8:31033971:GGG:G	donor_gain	1.0000
8:31033972:GG:G	donor_gain	1.0000
8:31033972:GGG:G	donor_gain	1.0000
8:31033972:GGGT:G	donor_loss	1.0000
8:31033973:GG:G	donor_gain	1.0000
8:31033974:G:GA	donor_loss	1.0000
8:31033974:G:GG	donor_gain	1.0000
8:31033975:T:A	donor_loss	1.0000
8:31058539:GAAAG:G	donor_gain	1.0000
8:31058540:AAAG:A	donor_loss	1.0000
8:31058544:G:GG	donor_gain	1.0000
8:31058545:T:A	donor_loss	1.0000
8:31059133:T:TA	acceptor_gain	1.0000
8:31059141:A:AG	acceptor_gain	1.0000
8:31059144:A:AG	acceptor_gain	1.0000
8:31059145:A:G	acceptor_gain	1.0000
8:31059262:TTAGG:T	donor_loss	1.0000
8:31059266:G:GC	donor_loss	1.0000
8:31059266:G:GG	donor_gain	1.0000
8:31059267:TAAG:T	donor_loss	1.0000
8:31067031:A:AG	acceptor_gain	1.0000
8:31067031:AGCT:A	acceptor_gain	1.0000
8:31067032:G:GG	acceptor_gain	1.0000
8:31067032:GCT:G	acceptor_gain	1.0000
8:31067032:GCTG:G	acceptor_gain	1.0000
8:31067032:GCTGA:G	acceptor_gain	1.0000
8:31067183:G:GG	donor_gain	1.0000
8:31076168:CCTAG:C	acceptor_loss	1.0000
8:31076171:A:AG	acceptor_gain	1.0000
8:31076171:A:T	acceptor_loss	1.0000

AlphaMissense

9551 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:31090845:A:C	S578R	0.997
8:31090847:T:A	S578R	0.997
8:31090847:T:G	S578R	0.997
8:31100873:A:T	E669V	0.997
8:31088959:T:C	F549S	0.994
8:31090939:T:C	L609P	0.994
8:31111628:C:A	A701E	0.994
8:31120264:T:C	F824L	0.994
8:31120266:T:A	F824L	0.994
8:31120266:T:G	F824L	0.994
8:31120356:A:C	R854S	0.994
8:31120356:A:T	R854S	0.994
8:31100864:C:A	A666D	0.993
8:31100873:A:C	E669A	0.993
8:31100875:G:C	A670P	0.993
8:31090840:G:T	G576V	0.992
8:31090842:A:C	K577Q	0.992
8:31100888:C:T	S674F	0.992
8:31100905:T:C	F680L	0.992
8:31100907:T:A	F680L	0.992
8:31100907:T:G	F680L	0.992
8:31088958:T:C	F549L	0.991
8:31088960:T:A	F549L	0.991
8:31088960:T:G	F549L	0.991
8:31090840:G:A	G576E	0.991
8:31090843:A:T	K577M	0.991
8:31100876:C:A	A670D	0.991
8:31111637:C:A	A704D	0.991
8:31120355:G:C	R854T	0.991
8:31120284:A:C	K830N	0.990

dbSNP variants (sampled 300 via entrez): RS1000021631 (8:31171093 G>A), RS1000024327 (8:31066012 G>T), RS1000041139 (8:31125642 A>G), RS1000049543 (8:31168122 G>A), RS1000099085 (8:31034236 T>C), RS1000145028 (8:31122120 A>T), RS1000164908 (8:31047376 C>A), RS1000194058 (8:31095532 A>G), RS1000258400 (8:31108016 A>G), RS1000298415 (8:31045938 G>A), RS1000398652 (8:31147578 T>C), RS1000409619 (8:31154423 G>A), RS1000488592 (8:31139172 A>G), RS1000496277 (8:31129978 C>T), RS1000503255 (8:31032714 A>G)

Disease associations

OMIM: gene MIM:604611 | disease phenotypes: MIM:277700, MIM:301000, MIM:167000, MIM:116200, MIM:125853, MIM:155255

GenCC curated gene-disease

Disease	Classification	Inheritance
Werner syndrome	Definitive	Autosomal recessive
osteosarcoma	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Werner syndrome	Definitive	AR

Mondo (8): Werner syndrome (MONDO:0010196), Wiskott-Aldrich syndrome (MONDO:0010518), ovarian cancer (MONDO:0008170), breast cancer (MONDO:0007254), cataract (MONDO:0005129), type 2 diabetes mellitus (MONDO:0005148), medulloblastoma (MONDO:0007959), osteosarcoma (MONDO:0009807)

Orphanet (4): Werner syndrome (Orphanet:902), Wiskott-Aldrich syndrome (Orphanet:906), Rare ovarian cancer (Orphanet:213500), Medulloblastoma (Orphanet:616)

HPO phenotypes

84 total (30 of 84 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000035	Abnormal testis morphology
HP:0000135	Hypogonadism
HP:0000144	Decreased fertility
HP:0000275	Narrow face
HP:0000320	Bird-like facies
HP:0000444	Convex nasal ridge
HP:0000518	Cataract
HP:0000546	Retinal degeneration
HP:0000765	Abnormal thorax morphology
HP:0000819	Diabetes mellitus
HP:0000822	Hypertension
HP:0000855	Insulin resistance
HP:0000869	Secondary amenorrhea
HP:0000934	Chondrocalcinosis
HP:0000939	Osteoporosis
HP:0000962	Hyperkeratosis
HP:0001387	Joint stiffness
HP:0001533	Slender build
HP:0001601	Laryngomalacia
HP:0001608	Abnormality of the voice
HP:0001620	Abnormally high-pitched voice
HP:0001635	Congestive heart failure
HP:0001658	Myocardial infarction
HP:0001838	Rocker bottom foot
HP:0002155	Hypertriglyceridemia
HP:0002209	Sparse scalp hair
HP:0002211	White forelock
HP:0002216	Premature graying of hair
HP:0002293	Alopecia of scalp

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000089_3	Exercise treadmill test traits	6.000000e-06
GCST002846_6	Lifespan	6.000000e-08
GCST003518_18	Daytime sleep phenotypes	2.000000e-06
GCST004049_4	Cough in response to angiotensin-converting enzyme inhibitor drugs	2.000000e-06
GCST005316_79	Intelligence (MTAG)	2.000000e-08
GCST006999_2	Logical memory (immediate recall) in mild cognitive impairment	2.000000e-08
GCST007000_4	Logical memory (delayed recall) in mild cognitive impairment	2.000000e-07
GCST007565_132	Morning person	2.000000e-13
GCST007576_11	Chronotype	2.000000e-13
GCST008504_2	Fasting glucose change (long-term)	3.000000e-07
GCST009391_1027	Metabolite levels	4.000000e-06
GCST009391_997	Metabolite levels	8.000000e-06
GCST012489_149	Heel bone mineral density x serum urate levels interaction	3.000000e-08

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004328	exercise test
EFO:0007828	daytime rest measurement
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0004337	intelligence
EFO:0004874	memory performance
EFO:0008328	chronotype measurement
EFO:0010540	thiamine measurement
EFO:0010475	deoxycholate measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D002386	Cataract	C11.510.245
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D008527	Medulloblastoma	C04.557.465.625.600.380.515; C04.557.465.625.600.590.500; C04.557.470.670.380.515; C04.557.470.670.590.500; C04.557.580.625.600.380.515; C04.557.580.625.600.590.500
D012516	Osteosarcoma	C04.557.450.565.575.650; C04.557.450.795.620
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D014898	Werner Syndrome	C16.320.925; C18.452.284.960
D014923	Wiskott-Aldrich Syndrome	C15.378.100.100.970; C15.378.243.750.605.900; C15.378.463.960; C15.378.553.546.605.900; C16.320.099.970; C16.320.322.937; C16.320.798.875; C20.673.627.900; C20.673.795.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2146312 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 350 (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
CHEMBL1091250	INDIGOTINDISULFONATE	4	340
CHEMBL6068555	HRO-761	1	10

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1346044	WRN		0.00	0
rs2725335	PURG, WRN		0.00	0
rs1801195	WRN		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 3.6.4.12 RecQ helicases family

Most potent curated ligand interactions (7 total), top 7:

Ligand	Action	Affinity	Parameter
MOMA-341	Inhibition	11.3	pIC50
H3B-968	Inhibition	8.0	pIC50
H3B-960	Inhibition	7.49	pKi
romoverlib	Inhibition	7.0	pIC50
VVD-133214	Inhibition	6.89	pIC50
ML216	Inhibition	5.57	pIC50
compound 6 [PMID: 38134034]	Inhibition	4.91	pIC50

Binding affinities (BindingDB)

401 measured of 403 human assays (870 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(1,3-dihydroisobenzofuran-5-yl)-5-ethyl-6-(4-(5-hydroxy-6-(3-methoxyazetidin-1-yl)pyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	3 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
2-[2-(dimethylamino)-5-ethyl-6-(4-{3-hydroxy-4-oxo-6H,7H,9H-pyrimido[2,1-c][1,4]oxazine-2-carbonyl}piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]acetamide	IC50	13.4 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	14.6 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	16 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2H-indazol-5-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	16 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl]-2-(5-ethyl-2-{4-fluoropyrazolo[1,5-a]pyridin-5-yl}-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl]-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetamide	IC50	18 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-2-chloro-4-(trifluoromethyl) phenylacetamide	IC50	19 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(6-fluoropyrazolo[1,5-a]pyridin-5-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	19 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-2-chloro-4-(trifluoromethyl)phenylacetamide	IC50	19 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl]{2-[p-(1-azetidinylsulfonyl)phenyl]-6-ethyl-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl)carbonyl]-1-piperazinyl}-4-oxo-1,3,3a,7-tetraaza-7-indenyl}acetamide	IC50	19 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(5,8-difluoroquinolin-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	19 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-(1,3-dihydro-2-benzofuran-5-yl)-5-ethyl-6-(4-{3-hydroxy-4-oxo-6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carbonyl}piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide	IC50	19 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
2-[2-(2,3-dihydro-1,4-benzodioxin-5-yl)-5-ethyl-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl]-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]acetamide	IC50	19.3 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(1-methyl-1H-indazol-5-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	20 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-2-chloro-4-(trifluoromethyl)phenylacetamide	IC50	20 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(1,3-dihydroisobenzofuran-5-yl)-5-ethyl-6-(4-(4-hydroxyisoxazole-3-carbonyl) piperazin-1-yl)-7-oxo- [1,2,4] triazolo[1,5-a] pyrimidin-4(7H)-yl)acetamide	IC50	20 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
2-(6-(4-(3H-imidazo[4,5-c]pyridine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide	IC50	20.1 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-7-oxo-[1,2,4] triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	21 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl]-2-{5-ethyl-6-[4-(5-hydroxy-6-methyl pyrimidine-4-carbonyl)piperazin-1-yl]-2-{4-methylpyrazolo[1,5-a]pyridin-5-yl}-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}acetamide	IC50	21 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl]{2-[p-(aminosulfonylamino)phenyl]-6-ethyl-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl)carbonyl]-1-piperazinyl}-4-oxo-1,3,3a,7-tetraaza-7-indenyl}acetamide	IC50	21 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
2-(2-(benzo[d][1,3]dioxol-5-yl)-5-ethyl-6-(4-(3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide	IC50	21.5 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
2-(6-(4-(3H-imidazo[4,5-c]pyridine-4-carbonyl)piperazin-1-yl)-2-(dimethylamino)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)acetamide	IC50	21.8 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl]-2-{5-ethyl-2-[(2R)-6-fluoro-2-methyl-2,3-dihydro-1-benzofuran-5-yl]-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl]-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}acetamide	IC50	22 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-(7-fluoro-3,4-dihydro-1H-2-benzopyran-6-yl)-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl) piperazin-1-yl]-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide	IC50	22 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl][2-(2,1-benzisothiazol-5-yl)-6-ethyl-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl)carbonyl]-1-piperazinyl}-4-oxo-1,3,3a,7-tetraaza-7-indenyl]acetamide	IC50	22 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methyl-2H-indazol-5-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	23 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-2-chloro-4-(trifluoromethyl)phenylacetamide	IC50	23 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl) phenyl] [6-ethyl-2-(6-fluoro-2-methyl-2H-indazol-5-yl)-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl) carbonyl]-1-piperazinyl}-4-oxo-1,3,3a,7-tetraaza-7-indenyl]acetamide	IC50	23 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-2-chloro-4-(trifluoromethyl)phenylacetamide	IC50	23 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl) phenyl] (6-ethyl-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl) carbonyl]-1-piperazinyl}-4-oxo-2-(2-oxo-6-quinolyl)-1,3,3a,7-tetraaza-7-indenyl)acetamide	IC50	23 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	23.6 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl]-2-{5-ethyl-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl) piperazin-1-yl]-2-{7-methylpyrazolo[1,5-a]pyridin-5-yl}-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}acetamide	IC50	24 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
(S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(6-fluoro-1-methoxy-2,3-dihydro-1H-inden-5-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	24 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl) phenyl] {2-[2-(difluoromethyl)-2H-indazol-5-yl]-6-ethyl-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl) carbonyl]-1-piperazinyl}-4-oxo-1,3,3a,7-tetraaza-7-indenyl}acetamide	IC50	24 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-2-chloro-4-(trifluoromethyl)phenylacetamide	IC50	24 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl) phenyl] (6-ethyl-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl) carbonyl]-1-piperazinyl}-4-oxo-2-(6-quinazolinyl)-1,3,3a,7-tetraaza-7-indenyl)acetamide	IC50	24 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl) phenyl] (6-ethyl-3’-fluoro-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl) carbonyl]-1-piperazinyl}-4-oxo-7H-1,1’,3,3a,7,7a’-hexaaza-2,5’-biindenyl-7-yl)acetamide	IC50	24 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
2-(2-(benzo[d][1,3]dioxol-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide	IC50	24.9 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-(6-fluoro-1,3-dihydro-2-benzofuran-5-yl)-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl]-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide	IC50	25 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	25 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl]-2-{5-ethyl-2-[(2S)-6-fluoro-2-methyl-2,3-dihydro-1-benzofuran-5-yl]-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl]-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}acetamide	IC50	25 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-2-chloro-4-(trifluoromethyl)phenylacetamide	IC50	25 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
2-(2-(2-aminobenzo[d]oxazol-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide	IC50	25 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-ethyl-2H-indazol-5-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide	IC50	25 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl) phenyl] (6-ethyl-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl) carbonyl]-1-piperazinyl}-2-(1-methyl-2-oxo-3,4-dihydro-6-quinolyl)-4-oxo-1,3,3a,7-tetraaza-7-indenyl)acetamide	IC50	25 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl) phenyl] (6-ethyl-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl) carbonyl]-1-piperazinyl}-4-oxo-2-(2-oxo-5-indolinyl)-1,3,3a,7-tetraaza-7-indenyl)acetamide	IC50	25 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
[4-(7-{[N-(2-chloro-4-(trifluoromethyl)phenyl)carbamoyl]methyl}-6-ethyl-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl)carbonyl]-1-piperazinyl}-4-oxo-1,3,3a,7-tetraaza-2-indenyl)phenoxy]acetic acid	IC50	25 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
2-{6-[(3aR,7aS)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-hexahydro-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-(1,3-dihydro-2-benzofuran-5-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide	IC50	25 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
(7R,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropy rrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide	IC50	25.5 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME
N-[2-chloro-4-(trifluoromethyl)phenyl][6-ethyl-2-(6-fluoro-2,3-dihydro-1-benzofuran-5-yl)-5-{4-[(5-hydroxy-6-methyl-4-pyrimidinyl)carbonyl]-1-piperazinyl}-4-oxo-1,3,3a,7-tetraaza-7-indenyl]acetamide	IC50	26 nM	WO-2025049746: COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME

ChEMBL bioactivities

161 potent at pChembl≥5 of 197 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.64	IC50	0.228	nM	CHEMBL6191148
8.82	IC50	1.5	nM	CHEMBL6193303
8.73	Kd	1.85	nM	CHEMBL6193169
8.72	IC50	1.9	nM	CHEMBL6190576
8.72	IC50	1.9	nM	CHEMBL6189893
8.72	IC50	1.9	nM	CHEMBL6192394
8.70	IC50	2	nM	CHEMBL6192214
8.70	IC50	2	nM	CHEMBL6192876
8.40	IC50	4	nM	CHEMBL6193169
8.30	IC50	5	nM	CHEMBL6189670
8.30	IC50	5	nM	CHEMBL6190279
8.30	IC50	5	nM	CHEMBL6190738
8.30	IC50	5	nM	CHEMBL6191990
8.30	IC50	5	nM	CHEMBL6189544
8.10	IC50	8	nM	CHEMBL6190298
8.10	IC50	8	nM	CHEMBL6190364
8.05	IC50	9	nM	CHEMBL6190262
8.05	IC50	9	nM	CHEMBL6192541
8.05	IC50	9	nM	CHEMBL6189085
8.00	IC50	10	nM	CHEMBL6188722
7.93	IC50	11.7	nM	CHEMBL6145192
7.92	IC50	12	nM	CHEMBL6143539
7.85	IC50	14	nM	CHEMBL6191411
7.82	IC50	15	nM	CHEMBL6189870
7.80	IC50	16	nM	CHEMBL6189964
7.79	IC50	16.1	nM	CHEMBL6149499
7.79	IC50	16.2	nM	CHEMBL6143893
7.77	IC50	17	nM	CHEMBL6166435
7.77	IC50	17	nM	CHEMBL6190558
7.76	IC50	17.2	nM	CHEMBL6145855
7.76	IC50	17.3	nM	CHEMBL6145192
7.75	IC50	17.7	nM	CHEMBL6145855
7.75	IC50	17.8	nM	CHEMBL6167823
7.71	IC50	19.3	nM	CHEMBL6142101
7.71	IC50	19.4	nM	CHEMBL6133237
7.70	IC50	19.8	nM	CHEMBL6166435
7.66	IC50	21.8	nM	CHEMBL6142101
7.65	IC50	22.6	nM	CHEMBL6120422
7.64	IC50	23.1	nM	CHEMBL6147675
7.64	IC50	23.1	nM	CHEMBL6167823
7.63	IC50	23.5	nM	CHEMBL6149499
7.60	IC50	25.1	nM	CHEMBL6168099
7.59	IC50	25.4	nM	CHEMBL6133237
7.57	IC50	27.2	nM	CHEMBL6162993
7.55	IC50	28.3	nM	CHEMBL6168099
7.54	IC50	29	nM	CHEMBL6189651
7.54	IC50	29	nM	CHEMBL6189789
7.53	IC50	29.8	nM	HRO-761
7.51	IC50	30.8	nM	HRO-761
7.51	IC50	31	nM	CHEMBL6192156

PubChem BioAssay actives

16 with measured affinity, of 63 total; 14 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
2-(3-hydroxy-5-sulfo-1H-indol-2-yl)-3-oxoindole-5-sulfonic acid	2139691: Inhibition of recombinant human WRN unwinding activity by immunosorbent-based helicase unwinding assay	ic50	0.2000	uM
3,4-dichloro-1-[3-(3,4-dichloro-2,5-dioxopyrrol-1-yl)-2,2-dimethylpropyl]pyrrole-2,5-dione	2139690: Inhibition of WRN (unknown origin)	ic50	0.2300	uM
1-(4-bromo-3-cyanophenyl)-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea	771543: Inhibition of WRN (unknown origin) by gel-based DNA unwinding assay	ic50	1.1000	uM
1-(4-chloro-3-cyanophenyl)-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea	771543: Inhibition of WRN (unknown origin) by gel-based DNA unwinding assay	ic50	1.6000	uM
1-(3-cyano-4-fluorophenyl)-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea	771543: Inhibition of WRN (unknown origin) by gel-based DNA unwinding assay	ic50	2.2000	uM
6-methoxy-3-(5-phenyl-1,2,4-oxadiazol-3-yl)-1H-quinolin-2-one	2139690: Inhibition of WRN (unknown origin)	ic50	2.3000	uM
2-[[5-(4-ethoxyphenyl)thiophen-2-yl]-(2-hydroxy-4,4-dimethyl-6-oxocyclohexen-1-yl)methyl]-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one	2107063: Inhibition of WRN in human HCT-116 cells	ic50	2.3050	uM
1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea	771543: Inhibition of WRN (unknown origin) by gel-based DNA unwinding assay	ic50	2.7000	uM
1-(3,4-dibromophenyl)-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea	771543: Inhibition of WRN (unknown origin) by gel-based DNA unwinding assay	ic50	2.9000	uM
(2,5-dioxopyrrol-1-yl)methyl propanoate	1440489: Inhibition of recombinant WRN (unknown origin) helicase activity expressed in baculovirus expression system using forked duplex DNA as substrate after 15 mins by polyacrylamide gel electrophoresis	ic50	3.0000	uM
3-hydroxy-2-[(2-hydroxy-4,4-dimethyl-6-oxocyclohexen-1-yl)-[5-(2-phenylethyl)thiophen-2-yl]methyl]-5,5-dimethylcyclohex-2-en-1-one	2107063: Inhibition of WRN in human HCT-116 cells	ic50	3.0190	uM
1-(3,4-dichlorophenyl)-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea	771543: Inhibition of WRN (unknown origin) by gel-based DNA unwinding assay	ic50	3.4000	uM
1-[3-cyano-4-(1H-pyrazol-4-yl)phenyl]-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea	771543: Inhibition of WRN (unknown origin) by gel-based DNA unwinding assay	ic50	7.1000	uM
3-[[2-[(E)-[1-[2-(4-methylanilino)-2-oxoethyl]-2,5-dioxoimidazolidin-4-ylidene]methyl]phenoxy]methyl]benzoic acid	2139691: Inhibition of recombinant human WRN unwinding activity by immunosorbent-based helicase unwinding assay	ic50	9.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
hydroquinone	increases response to substance, affects reaction, increases acetylation, decreases reaction, increases cleavage (+3 more)	4
Valproic Acid	increases expression, affects expression, decreases expression	4
chromium hexavalent ion	decreases response to substance, affects localization, increases response to substance	2
Resveratrol	affects localization, affects cotreatment, increases expression	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Benzene	increases response to substance, affects response to substance	2
Cisplatin	decreases expression, decreases response to substance, increases expression	2
Cyclosporine	increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
O-(6)-methylguanine	decreases response to substance	1
arsenite	decreases reaction, affects binding	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
8-hydroxyguanine	decreases response to substance	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	decreases expression	1
1-(propoxymethyl)maleimide	decreases activity	1
Arsenic Trioxide	increases expression	1
Amsacrine	increases response to substance	1
Arsenic	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1

ChEMBL screening assays

32 unique, capped per target: 30 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2114796	Functional	PubChem BioAssay. qHTS for Inhibitors of WRN Helicase. (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL2428260	Binding	Inhibition of WRN (unknown origin) by gel-based DNA unwinding assay	Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom helicase. — Bioorg Med Chem Lett

Cellosaurus cell lines

86 cell lines: 59 transformed cell line, 11 induced pluripotent stem cell, 8 finite cell line, 6 cancer cell line, 2 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7BR	WS5801	Transformed cell line	Male
CVCL_A7BS	WS6501	Transformed cell line	Female
CVCL_A7BT	WS0101	Transformed cell line	Male
CVCL_A7BU	WS2101	Transformed cell line	Female
CVCL_A7BV	WS11001	Transformed cell line	Female
CVCL_A7BW	WS23702	Transformed cell line	Male
CVCL_A7BX	WS23703	Transformed cell line	Male
CVCL_A7BY	WS10402	Transformed cell line	Female
CVCL_A7BZ	WS24002	Transformed cell line	Female
CVCL_A7CA	WS9101	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01669369	PHASE4	UNKNOWN	Clinical Trial of Lithium Carbonate Combined With Neo-adjuvant Chemotherapy to Treat Osteosarcoma
NCT04854018	PHASE4	COMPLETED	Indo-cyanine Green (ICG) in Paediatric Oncology MIS
NCT01289847	PHASE4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00727961	PHASE4	COMPLETED	A Study to Evaluate Efficacy and Tolerance of Caelyx in Patients With Epithelial Ovarian Cancer. (Study P04072)(COMPLETED)
NCT00740116	PHASE4	COMPLETED	Tranexamic Acid in Surgery of Advanced Ovarian Cancer
NCT00817479	PHASE4	COMPLETED	Tumor Gene Expression in Women With Ovarian Cancer
NCT01432015	PHASE4	COMPLETED	Fosaprepitant Versus Aprepitant in the Prevention of Chemotherapy Induced Nausea and Vomiting
NCT01706120	PHASE4	UNKNOWN	Study of Clinical and Biological Prognostic Factors in Patients With Ovarian Cancer Receiving Carboplatin +Paclitaxel With Bevacizumab
NCT01932125	PHASE4	COMPLETED	An Interventional Study of Avastin (Bevacizumab) in Patients With Advanced/Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT01953107	PHASE4	COMPLETED	Oral Iron vs. Placebo in Newly Diagnosed Gynecologic Oncology Patients Who Are Surgical Candidates.
NCT02035345	PHASE4	TERMINATED	Slowed Carboplatin Infusion for Ovarian Cancer Patients Receiving Carboplatin Re-Treatment
NCT02243059	PHASE4	WITHDRAWN	Magnetic Resonance Imaging for Lymph Node Staging in Ovarian Cancer
NCT03164980	PHASE4	TERMINATED	QoL-Comparison Between Trabectedin/PLD and Pt-based Therapy in Patients With Pt-sensitive Recurrent Ovarian Cancer
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03543462	PHASE4	COMPLETED	Diaphragmatic Resection And Gynecological Ovarian Neoplasm
NCT03752216	PHASE4	COMPLETED	NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.
NCT03858166	PHASE4	TERMINATED	Efficacy and Safety of PEG-rhG-CSF Secondary Prophylaxis vs. Therapeutic Administration in Patients With Ovarian Cancer
NCT04024254	PHASE4	COMPLETED	A Study of Serum Folate Levels in Patients Treated With Olaparib
NCT04330040	PHASE4	COMPLETED	Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer
NCT04352439	PHASE4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT05187208	PHASE4	UNKNOWN	PARP Inhibitor Oral Maintenance in Low-Risk Ovarian Cancer
NCT05606692	PHASE4	RECRUITING	Influences of Propofol and Sevoflurane Anesthesia in Ovarian Cancer (Anesthetics)
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06412120	PHASE4	RECRUITING	Study Evaluating Safety, Tolerability, and Metabolism of Niraparib
NCT06871787	PHASE4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT06887933	PHASE4	NOT_YET_RECRUITING	A Trial to Evaluate the Safety of Niraparib Tablets in Adult Female Participants With Advanced or Relapsed Epithelial Ovarian Cancer
NCT07469202	PHASE4	NOT_YET_RECRUITING	CYTALUX Dose Extension Study
NCT00001217	PHASE3	COMPLETED	Osteosarcoma Study #2: A Randomized Trial of Pre-Surgical Chemotherapy vs. Immediate Surgery and Adjuvant Chemotherapy in the Treatment of Non-Metastatic Osteosarcoma. A Pediatric Oncology Group Phase III Study
NCT00134030	PHASE3	COMPLETED	Combination Chemotherapy, PEG-Interferon Alfa-2b, and Surgery in Treating Patients With Osteosarcoma
NCT00180908	PHASE3	COMPLETED	Comparison of High-Dose Methotrexate (HDM) Plus Doxorubicin to HDM Plus Etoposide-Ifosfamide in Osteosarcoma Children
NCT01176981	PHASE3	COMPLETED	Outpatient Administration of High Dose Methotrexate (HD MTX) in Patients With Osteosarcoma
NCT01987596	PHASE3	TERMINATED	Study of Fixed vs. Flexible Filgrastim to Accelerate Bone Marrow Recovery After Chemotherapy in Children With Cancer
NCT05024253	PHASE3	COMPLETED	Perioperative Use of Tranexamic (TXA) in Bone Tumor Surgery Will Change in Blood Loss and Transfusion Requirements.
NCT05235165	PHASE3	RECRUITING	Thoracotomy Versus Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma
NCT05328258	PHASE3	RECRUITING	Use of GnRHa During Chemotherapy for Fertility Protection
NCT06935409	PHASE3	ACTIVE_NOT_RECRUITING	Study of HS-20093 Versus Gemcitabine in Combination With Docetaxel in Treatment of Osteosarcoma After Previous Second-line Treatment Failure
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00278954	PHASE3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.