TDP2

Summary

TDP2 (tyrosyl-DNA phosphodiesterase 2, HGNC:17768) is a protein-coding gene on chromosome 6p22.3, encoding Tyrosyl-DNA phosphodiesterase 2 (O95551). DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5’-phosphodiester bond, giving rise to DNA with a free 5’ phosphate. It is a selective cancer dependency (DepMap: 13.4% of cell lines).

This gene encodes a member of a superfamily of divalent cation-dependent phosphodiesterases. The encoded protein associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor associated factors (TRAFs), and inhibits nuclear factor-kappa-B activation. This protein has sequence and structural similarities with APE1 endonuclease, which is involved in both DNA repair and the activation of transcription factors.

Source: NCBI Gene 51567 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia, autosomal recessive 23 (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 92 total — 11 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 13.4% of screened cell lines
• MANE Select transcript: NM_016614

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17768
Approved symbol	TDP2
Name	tyrosyl-DNA phosphodiesterase 2
Location	6p22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111802
Ensembl biotype	protein_coding
OMIM	605764
Entrez	51567

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000341060, ENST00000378198, ENST00000478285, ENST00000478507, ENST00000480495, ENST00000874523, ENST00000874524, ENST00000954493

RefSeq mRNA: 1 — MANE Select: NM_016614 NM_016614

CCDS: CCDS4557

Canonical transcript exons

ENST00000378198 — 7 exons

Exon	Start	End
ENSE00000615962	24658561	24658734
ENSE00000693189	24654412	24654530
ENSE00001476609	24649979	24651069
ENSE00001896291	24666698	24666899
ENSE00003592092	24666526	24666611
ENSE00003606958	24657812	24657903
ENSE00003680876	24652983	24653153

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.0020 / max 564.3900, expressed in 1815 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72195	18.9667	1808
72192	6.9081	1108
72196	1.0588	557
72193	0.9275	400
72191	0.7134	325
72194	0.3408	155
72198	0.0681	28
72199	0.0186	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.74	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.60	gold quality
colonic mucosa	UBERON:0000317	99.58	gold quality
ileal mucosa	UBERON:0000331	99.10	gold quality
rectum	UBERON:0001052	98.40	gold quality
duodenum	UBERON:0002114	98.39	gold quality
mucosa of transverse colon	UBERON:0004991	97.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.43	gold quality
palpebral conjunctiva	UBERON:0001812	97.31	gold quality
nephron tubule	UBERON:0001231	97.01	gold quality
islet of Langerhans	UBERON:0000006	96.80	gold quality
jejunum	UBERON:0002115	96.52	gold quality
germinal epithelium of ovary	UBERON:0001304	96.51	gold quality
secondary oocyte	CL:0000655	96.42	gold quality
visceral pleura	UBERON:0002401	96.26	gold quality
small intestine	UBERON:0002108	96.18	gold quality
transverse colon	UBERON:0001157	96.03	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.97	gold quality
parietal pleura	UBERON:0002400	95.93	gold quality
pleura	UBERON:0000977	95.84	gold quality
tibia	UBERON:0000979	95.74	gold quality
amniotic fluid	UBERON:0000173	95.58	gold quality
kidney epithelium	UBERON:0004819	95.58	gold quality
bronchial epithelial cell	CL:0002328	95.54	gold quality
seminal vesicle	UBERON:0000998	95.51	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.49	gold quality
colonic epithelium	UBERON:0000397	95.45	gold quality
cauda epididymis	UBERON:0004360	95.43	gold quality
epithelium of nasopharynx	UBERON:0001951	95.38	gold quality
blood	UBERON:0000178	95.36	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	16.20
E-ANND-3	yes	7.18
E-GEOD-100618	no	474.14
E-GEOD-75367	no	286.13
E-MTAB-6524	no	96.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting TDP2, 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-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-4477B	99.23	70.49	1733

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 38)

• interacts with ETS1 and modulates its transcriptional function (PMID:12743594)
• a significant association with (TTRAP)on reading and spelling ability was observed (PMID:17597587)
• TTRAP is a novel PML nuclear body protein. (PMID:18706885)
• These results suggest an active role of DJ-1 missense mutants in the control of cell death and position TTRAP as a new player in the arena of neurodegeneration. (PMID:19023331)
• This is the first time that TTRAP has been shown to interact with HIV-1 integrase and facilitate lentiviral vector integration. (PMID:19580783)
• PhiC31 integrase interacts with TTRAP and inhibits the NFkappaB activation. (PMID:19757154)
• TTRAP is the first human 5’-tyrosyl DNA phosphodiesterase to be identified, and we suggest that this enzyme is denoted tyrosyl DNA phosphodiesterase-2 (TDP2). (PMID:19794497)
• an important mechanism for resistance to Top2-induced chromosome breakage and the possibility that TDP2 is a significant factor in cancer development and treatment (PMID:21030584)
• EAPII is an oncogenic factor and the activation of MAPK-ERK signaling pathway by EAPII may contribute to lung cancer development. (PMID:21478903)
• findings suggest a previously unidentified function for TTRAP and nucleolar cavities in ribosome biogenesis under stress. (PMID:21921940)
• both FOXP2 and KIAA0319/TTRAP/THEM2 genes play an important role in human language development, but probably through different cerebral pathways. (PMID:22262880)
• Magnesium is indispensable for a 5’-tyrosyl DNA phosphodiesterase activity. (PMID:22405347)
• Biochemical characterization of human tyrosyl-DNA phosphodiesterase 2 (TDP2/TTRAP): a Mg(2+)/Mn(2+)-dependent phosphodiesterase specific for the repair of topoisomerase cleavage complexes. (PMID:22822062)
• VPg unlinkase activity in different mammalian cell lines correlates with their differential expression of TDP2. (PMID:22908287)
• Mutations in the 5’-tyrosyl-DNA phosphodiesterase activity of TTRAP,in particular TTRAP(E152A), showed decreased inhibitory activity on cell growth. (PMID:23433115)
• TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. (PMID:24658003)
• Proteolytic degradation of Top2 enables the processing of Top2.DNA and Top2.RNA covalent complexes by TDP2. (PMID:24808172)
• This article summarizes and compares the biochemistry, functions, and post-translational regulation of TDP1 and TDP2, as well as the relevance of TDP1 and TDP2 as determinants of response to anticancer agents (PMID:24856239)
• Data show that DNA-repair enzyme TDP2 knockdown in HepG2 cells significantly delays the conversion of relaxed circular DNA (RC-DNA) to covalently closed circular (ccc) DNA. (PMID:25201958)
• Study revealed a post-translational regulation of TDP2 activity and discovered a new role of ERK3 in increasing cancer cells’ DNA damage response and chemoresistance to Top2 inhibitors. (PMID:26701725)
• Both the genome instability and cell death of MRE11-null and MRE11-mutated H129N cells are significantly reversed by overexpression of Tdp2, an enzyme that eliminates covalent Top2 conjugates; thus, the essential role of Mre11 nuclease activity is likely to remove the DNA lesions. (PMID:27814490)
• TDP2 suppresses chromosome rearrangements induced by TOP2 and reduces TOP2-induced chromosome translocations that arise during gene transcription. (PMID:28794467)
• These findings uncover a ZNF451-TDP2-catalyzed and SUMO2-modulated pathway for direct resolution of TOP2 cleavage complex. (PMID:28912134)
• Data suggest that tyrosyl-DNA Phosphodiesterases 1 (TDP1) and 2 (TDP2) are promising therapeutic targets and their inhibitors are expected to significantly synergize the effects of current anti-tumor therapies [Review]. (PMID:29216365)
• TDP2 re-localizes from the nucleus to the cytoplasm of EMCV infected cells. (PMID:29353210)
• lack of TDP2 in the mitochondria reduces the mitochondria transcription levels in two different human cell lines. In addition to identifying a novel TDP2(S) isoform, our report demonstrates the presence and importance of both TDP2 isoforms in the mitochondria. (PMID:29438979)
• Data indicate that tyrosyl-DNA phosphodiesterase 2 (TDP2) alone does not remove DNA topoisomerase II (TOP2)-DNA complexes from genomic DNA in vitro and that depletion of TDP2 in cells does not slow the removal of TOP2-DNA complexes. (PMID:30011940)
• This article reviews TDP1 and TDP2 in the context of mitochondrial DNA repair. [review] (PMID:31226795)
• Effects of TDP2/VPg Unlinkase Activity on Picornavirus Infections Downstream of Virus Translation. (PMID:32023921)
• TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands. (PMID:32277721)
• Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2. (PMID:32356875)
• Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase 1 DNA-protein crosslinks and 3’-blocking lesions in the absence of tyrosyl-DNA phosphodiesterase 1 (TDP1). (PMID:32460231)
• Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23). (PMID:32651480)
• Untangling trapped topoisomerases with tyrosyl-DNA phosphodiesterases. (PMID:32653827)
• DNA and RNA Cleavage Complexes and Repair Pathway for TOP3B RNA- and DNA-Protein Crosslinks. (PMID:33378676)
• A novel non-sense mutation in TDP2 causes spinocerebellar ataxia autosomal recessive 23 accompanied by bilateral upward gaze; report of a case and review of the literature. (PMID:34606976)
• Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia. (PMID:37558815)
• Exploring the removal of Spo11 and topoisomerases from DNA breaks in S. cerevisiae by human Tyrosyl DNA Phosphodiesterase 2. (PMID:39236418)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tdp2b	ENSDARG00000035954
danio_rerio	tdp2a	ENSDARG00000069941
mus_musculus	Tdp2	ENSMUSG00000035958
rattus_norvegicus	Tdp2	ENSRNOG00000018246
caenorhabditis_elegans	tdpt-1	WBGENE00013405

Protein

Protein identifiers

Tyrosyl-DNA phosphodiesterase 2 — O95551 (reviewed: O95551)

Alternative names: 5’-tyrosyl-DNA phosphodiesterase, ETS1-associated protein 2, ETS1-associated protein II, TRAF and TNF receptor-associated protein, Tyrosyl-RNA phosphodiesterase, VPg unlinkase

All UniProt accessions (3): O95551, A0A384MDM5, X6R5A3

UniProt curated annotations — full annotation on UniProt →

Function. DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5’-phosphodiester bond, giving rise to DNA with a free 5’ phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. The 5’-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DNA double-strand breaks/DSBs without the need for nuclease activity, creating a ‘clean’ DSB with 5’-phosphate termini that are ready for ligation. Thereby, protects the transcription of many genes involved in neurological development and maintenance from the abortive activity of TOP2. Hydrolyzes 5’-phosphoglycolates on protruding 5’ ends on DSBs due to DNA damage by radiation and free radicals. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Acts as a regulator of ribosome biogenesis following stress. Also has 3’-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5’-tyrosyl-DNA phosphodiesterase in cells. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non-canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. (Microbial infection) Used by picornaviruses to remove the small polypeptide, VPg (virus Protein genome-linked, the primer for viral RNA synthesis), from the genomic RNA of the virus. Acts as a 5’-tyrosyl RNA phosphodiesterase and cleaves the covalent VPg-Tyr-RNA bond. This cleavage would play a role in viral replication and occur in viral replication vesicles, but would not act on viral mRNA.

Subunit / interactions. Interacts with TRAF2, TRAF3, TRAF5, TRAF6, TNFRSF8/CD30, TNFRSF5/CD40, TNFRSF1B/TNF-R75, ETS1, ETS2, FLI1, SMAD3 and ACVR1B/ALK4. (Microbial infection) Interacts with Hantaan hantavirus nucleoprotein. (Microbial infection) Interacts with Seoul hantavirus nucleoprotein.

Subcellular location. Nucleus. PML body. Nucleolus. Cytoplasm Cytoplasm.

Tissue specificity. Widely expressed. Highly expressed in various brain regions, including the frontal and occipital lobes, the hippocampus, the striatum and the cerebellum.

Post-translational modifications. Ubiquitinated by TRAF6.

Disease relevance. Spinocerebellar ataxia, autosomal recessive, 23 (SCAR23) [MIM:616949] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR23 patients manifest epilepsy, intellectual disability, and gait ataxia. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 magnesium or manganese ion per subunit.

Similarity. Belongs to the CCR4/nocturin family.

Isoforms (3)

UniProt ID	Names	Canonical?
O95551-1	1	yes
O95551-2	2
O95551-3	3

RefSeq proteins (1): NP_057698* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005135	Endo/exonuclease/phosphatase	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily
IPR051547	TDP2-like	Family

Pfam: PF03372, PF14555

UniProt features (69 total): strand 15, mutagenesis site 13, helix 9, region of interest 5, site 4, modified residue 4, sequence variant 4, sequence conflict 3, turn 3, cross-link 2, splice variant 2, binding site 2, chain 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6Q00	X-RAY DIFFRACTION	0.85
6Q01	X-RAY DIFFRACTION	0.85
5J3P	X-RAY DIFFRACTION	3.1
5INO	X-RAY DIFFRACTION	3.21
5J3S	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95551-F1	85.61	0.73

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 (5): 178 (interaction with 5’ end of substrate dna); 297 (interaction with 5’ end of substrate dna); 315 (interaction with 5’ end of substrate dna); 351 (interaction with 5’ end of substrate dna); 262 (proton donor/acceptor)

Ligand- & substrate-binding residues (2): 122; 152

Post-translational modifications (6): 1, 88, 92, 95, 23, 82

Mutagenesis-validated functional residues (13):

Position	Phenotype
88	abolishes function, but retains ability to interact with smad3; when associated with a-92.
92	abolishes function, but retains ability to interact with smad3; when associated with a-88.
120	strongly reduced phosphodiesterase activity.
152	loss of phosphodiesterase activity.
178	strongly decreased phosphodiesterase activity.
206	loss of phosphodiesterase activity.
262	loss of phosphodiesterase activity.
305	decreased phosphodiesterase activity.
316	strongly decreased phosphodiesterase activity.
350	strongly decreased phosphodiesterase activity.
351	loss of phosphodiesterase activity. delayed poliovirus replication in host cells.
351	loss of phosphodiesterase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)

MSigDB gene sets: 191 (showing top): HORIUCHI_WTAP_TARGETS_DN, TGCGCANK_UNKNOWN, GOMF_NUCLEASE_ACTIVITY, GOBP_NEUROGENESIS, PATIL_LIVER_CANCER, MUELLER_PLURINET, GOBP_DNA_DAMAGE_RESPONSE, SCHLOSSER_SERUM_RESPONSE_DN, GRASEMANN_RETINOBLASTOMA_WITH_6P_AMPLIFICATION, REACTOME_DNA_REPAIR, BERENJENO_TRANSFORMED_BY_RHOA_UP, GOMF_SINGLE_STRANDED_DNA_BINDING, GOCC_NUCLEAR_BODY, MOREAUX_MULTIPLE_MYELOMA_BY_TACI_DN, GOCC_PML_BODY

GO Biological Process (6): double-strand break repair (GO:0006302), cell surface receptor signaling pathway (GO:0007166), neuron development (GO:0048666), DNA repair (GO:0006281), DNA damage response (GO:0006974), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (13): magnesium ion binding (GO:0000287), single-stranded DNA binding (GO:0003697), transcription corepressor activity (GO:0003714), nuclease activity (GO:0004518), manganese ion binding (GO:0030145), tyrosyl-RNA phosphodiesterase activity (GO:0036317), 5’-tyrosyl-DNA phosphodiesterase activity (GO:0070260), DNA binding (GO:0003677), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872), tyrosyl-DNA phosphodiesterase activity (GO:0070259)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), aggresome (GO:0016235), nuclear body (GO:0016604), PML body (GO:0016605)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
DNA Double-Strand Break Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphoric diester hydrolase activity	2
nuclear lumen	2
cellular anatomical structure	2
intracellular membraneless organelle	2
DNA repair	1
signal transduction	1
neuron differentiation	1
cell development	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
metal ion binding	1
DNA binding	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
catalytic activity, acting on a nucleic acid	1
transition metal ion binding	1
catalytic activity, acting on RNA	1
tyrosyl-DNA phosphodiesterase activity	1
nucleic acid binding	1
molecular_function	1
binding	1
catalytic activity	1
cation binding	1
catalytic activity, acting on DNA	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
inclusion body	1
nucleoplasm	1
nuclear body	1

Protein interactions and networks

STRING

1128 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TDP2	ACOT13	Q9NPJ3	933
TDP2	KIAA0319	Q5VV43	930
TDP2	TDP1	Q9NUW8	913
TDP2	TOP2A	P11388	865
TDP2	DCDC2	Q9UHG0	863
TDP2	TOP2B	Q02880	818
TDP2	ZNF451	Q9Y4E5	768
TDP2	CD40	P25942	764
TDP2	TOP1	P11387	759
TDP2	APEX1	P27695	708
TDP2	DNAAF4	Q8WXU2	700
TDP2	SPRTN	Q9H040	678
TDP2	FEN1	P39748	649
TDP2	PNKP	Q96T60	626
TDP2	LIG1	P18858	589

IntAct

75 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
AZIN1	OAZ2	psi-mi:“MI:0914”(association)	0.670
TDP2	BLK	psi-mi:“MI:0915”(physical association)	0.560
TDP2	DNM2	psi-mi:“MI:0915”(physical association)	0.560
TDP2	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
TCEAL1	CHEK1	psi-mi:“MI:0914”(association)	0.530
PLA2G10	CHEK1	psi-mi:“MI:0914”(association)	0.530
RSBN1	SETD1A	psi-mi:“MI:0914”(association)	0.530
C19orf25	TDP2	psi-mi:“MI:0914”(association)	0.530
TDP2	BTBD2	psi-mi:“MI:0915”(physical association)	0.490
TDP2	GOLGA2	psi-mi:“MI:0915”(physical association)	0.490
TDP2	DVL2	psi-mi:“MI:0915”(physical association)	0.490
TDP2	TFIP11	psi-mi:“MI:0915”(physical association)	0.490
GOLGA2	TDP2	psi-mi:“MI:0915”(physical association)	0.490
DVL2	TDP2	psi-mi:“MI:0915”(physical association)	0.490
TFIP11	TDP2	psi-mi:“MI:0915”(physical association)	0.490
TDP2	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
TDP2	E6	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (109): TDP2 (Affinity Capture-MS), TDP2 (Affinity Capture-MS), TDP2 (Affinity Capture-MS), TDP2 (Affinity Capture-MS), TDP2 (Affinity Capture-MS), TDP2 (Affinity Capture-MS), TDP2 (Affinity Capture-MS), TDP2 (Affinity Capture-MS), TDP2 (Affinity Capture-MS), TDP2 (Two-hybrid), TDP2 (Affinity Capture-MS), DVL2 (Two-hybrid), TFIP11 (Two-hybrid), BTBD2 (Two-hybrid), GOLGA2 (Two-hybrid)

ESM2 similar proteins: A3KPF2, A5D8M0, A7YWI9, A8XU68, D3ZGS3, F1NW29, F1QG30, F4J2K2, F7ASZ0, M3XQV7, O23461, O45870, O60502, O74369, O80568, O93530, O95551, P32019, P40015, P45951, P58545, Q01968, Q08DF7, Q0V9P1, Q14191, Q24239, Q28FQ5, Q3T1H5, Q3TIU4, Q5U4V2, Q5XJA0, Q6AXQ5, Q6J5K9, Q6K881, Q6L8Q7, Q6NVF0, Q6ZPR6, Q7SYS9, Q7YTB0, Q80YE7

Diamond homologs: A5D8M0, A7YWI9, A8XU68, F1NW29, O95551, Q28FQ5, Q3T1H5, Q5XJA0, Q9JJX7, Q9XWG3

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
ACVR1B	“up-regulates activity”	TDP2	phosphorylation
TDP2	“up-regulates activity”	TRAF6	binding
MAPK6	“up-regulates activity”	TDP2	phosphorylation
TRAF6	“up-regulates activity”	TDP2	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	1
Uncertain significance	50
Likely benign	11
Benign	5

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1323684	NM_016614.3(TDP2):c.650del (p.Gly217fs)	Pathogenic
2041505	NM_016614.3(TDP2):c.400C>T (p.Arg134Ter)	Pathogenic
2139718	NM_016614.3(TDP2):c.390dup (p.Glu131fs)	Pathogenic
2197639	NM_016614.3(TDP2):c.392_395del (p.Glu131fs)	Pathogenic
226424	NM_016614.3(TDP2):c.425+1G>A	Pathogenic
226425	NM_016614.3(TDP2):c.413_414delinsAA (p.Ser138Ter)	Pathogenic
2442386	NM_016614.3(TDP2):c.949C>T (p.Arg317Ter)	Pathogenic
2598969	NM_016614.3(TDP2):c.580_581del (p.Gln194fs)	Pathogenic
4753868	NM_016614.3(TDP2):c.591del (p.Pro198fs)	Pathogenic
620174	NM_016614.3(TDP2):c.389C>G (p.Ser130Ter)	Pathogenic
812705	NM_016614.3(TDP2):c.636+3_636+6del	Pathogenic
1325184	NM_016614.3(TDP2):c.635_636+2del	Likely pathogenic

SpliceAI

838 predictions. Top by Δscore:

Variant	Effect	Δscore
6:24652978:CTCA:C	donor_loss	1.0000
6:24652979:TCA:T	donor_loss	1.0000
6:24652980:CA:C	donor_loss	1.0000
6:24652981:ACC:A	donor_loss	1.0000
6:24652982:CCT:C	donor_gain	1.0000
6:24653153:CCT:C	acceptor_loss	1.0000
6:24653154:C:T	acceptor_loss	1.0000
6:24653155:T:A	acceptor_loss	1.0000
6:24654410:A:AC	donor_gain	1.0000
6:24654411:C:CC	donor_gain	1.0000
6:24654411:CATG:C	donor_gain	1.0000
6:24654541:T:C	acceptor_gain	1.0000
6:24658560:CAAAG:C	donor_gain	1.0000
6:24658730:CAACA:C	acceptor_gain	1.0000
6:24658733:CA:C	acceptor_gain	1.0000
6:24658735:C:CC	acceptor_gain	1.0000
6:24666524:A:AC	donor_gain	1.0000
6:24666525:C:CC	donor_gain	1.0000
6:24666696:A:AC	donor_gain	1.0000
6:24666697:C:CC	donor_gain	1.0000
6:24666699:T:TA	donor_gain	1.0000
6:24666865:T:TA	donor_gain	1.0000
6:24651069:CCTGA:C	acceptor_loss	0.9900
6:24651071:T:C	acceptor_loss	0.9900
6:24652981:A:AC	donor_gain	0.9900
6:24652982:C:CC	donor_gain	0.9900
6:24652982:CCTCT:C	donor_gain	0.9900
6:24653150:TCAC:T	acceptor_gain	0.9900
6:24653151:CAC:C	acceptor_gain	0.9900
6:24653151:CACC:C	acceptor_gain	0.9900

AlphaMissense

2383 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:24650830:A:C	S349R	0.998
6:24650830:A:T	S349R	0.998
6:24650832:T:G	S349R	0.998
6:24650836:A:C	F347L	0.998
6:24650836:A:T	F347L	0.998
6:24650838:A:G	F347L	0.998
6:24650927:C:G	R317P	0.998
6:24650988:A:G	W297R	0.998
6:24650988:A:T	W297R	0.998
6:24652996:A:G	L265P	0.998
6:24652998:A:C	N264K	0.998
6:24652998:A:T	N264K	0.998
6:24653005:T:A	D262V	0.998
6:24654431:C:G	R206T	0.998
6:24657874:T:A	E152V	0.998
6:24658631:A:G	W119R	0.998
6:24658631:A:T	W119R	0.998
6:24650823:A:G	W352R	0.997
6:24650823:A:T	W352R	0.997
6:24650824:G:C	H351Q	0.997
6:24650824:G:T	H351Q	0.997
6:24650826:G:C	H351D	0.997
6:24650828:T:A	D350V	0.997
6:24650831:C:A	S349I	0.997
6:24650971:G:C	N302K	0.997
6:24650971:G:T	N302K	0.997
6:24653004:A:C	D262E	0.997
6:24653004:A:T	D262E	0.997
6:24654430:T:A	R206S	0.997
6:24654430:T:G	R206S	0.997

dbSNP variants (sampled 300 via entrez): RS1000050028 (6:24658266 T>A), RS1000101888 (6:24658091 G>A,C), RS1000145428 (6:24667097 C>G,T), RS1000289540 (6:24664674 T>C), RS1000330174 (6:24663491 T>C), RS1000370702 (6:24651570 A>C), RS1000562653 (6:24664073 G>A), RS1000658662 (6:24667826 C>T), RS1000749033 (6:24668243 G>A), RS1000933506 (6:24668455 A>C,G,T), RS1000939543 (6:24668014 C>G), RS1001055175 (6:24656905 G>C), RS1001265783 (6:24665963 T>A,C), RS1001286065 (6:24662540 C>T), RS1001636454 (6:24665710 A>G)

Disease associations

OMIM: gene MIM:605764 | disease phenotypes: MIM:616949

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia, autosomal recessive 23	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
spinocerebellar ataxia, autosomal recessive 23	Definitive	AR

Mondo (2): spinocerebellar ataxia, autosomal recessive 23 (MONDO:0014846), cerebellar ataxia (MONDO:0000437)

Orphanet (2): Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency (Orphanet:404493), Rare ataxia (Orphanet:102002)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001262	Excessive daytime somnolence
HP:0001290	Generalized hypotonia
HP:0001875	Decreased total neutrophil count
HP:0001999	Abnormal facial shape
HP:0002902	Hyponatremia
HP:0003388	Easy fatigability
HP:0011675	Arrhythmia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003209_6	Colorectal or endometrial cancer	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004230	endometrial neoplasm

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2169736 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 37,475 (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
CHEMBL265502	SURAMIN	3	36,848
CHEMBL15192	LAPACHONE	2	589
CHEMBL126159	LMP-744	1	38

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

Binding affinities (BindingDB)

153 measured of 176 human assays (226 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
4-methoxy-N-(6-methoxy-4H-indeno[1,2-d][1,3]thiazol-2-yl)benzamide	IC50	23 nM
MLS000585839	IC50	453 nM
4-[(E)-[3-(2-methylanilino)-4-oxo-1-naphthalenylidene]amino]sulfonylbenzoic acid	IC50	522 nM
3-[[(4E)-1-keto-4-tosylimino-2-naphthyl]amino]benzoic acid	IC50	524 nM
MLS000704754	IC50	528 nM
(NZ)-N-[3-(4-hydroxyanilino)-4-keto-1-naphthylidene]thiophene-2-sulfonamide	IC50	656 nM
3-[[(4E)-4-(2,4-dimethylphenyl)sulfonylimino-1-keto-2-naphthyl]amino]benzoic acid	IC50	919 nM
3-[[(4E)-4-(4-ethylphenyl)sulfonylimino-1-keto-2-naphthyl]amino]benzoic acid	IC50	926 nM
4-({(4Z)-1-oxo-4-[(phenylsulfonyl)imino]-1,4-dihydronaphthalen-2-yl}amino)benzoic acid	IC50	967 nM
MLS000767219	IC50	1010 nM
SMR000516584	IC50	1270 nM
cid_738951	IC50	1380 nM
6-bromo-3-(2-methoxyanilino)-2H-isoquinolin-1-one	IC50	1510 nM
MLS000588669	IC50	1610 nM
(2Z)-1,3-diketo-2-[(5-methyl-2-furyl)methylene]indane-5-carboxylic acid	IC50	1650 nM
1,6-dimethyl-3-propyl-pyrimido[5,4-e][1,2,4]triazine-5,7-dione	EC50	1770 nM
MLS002608219	IC50	2020 nM
cid_367783	IC50	2080 nM
4-piperidin-1-ylnaphthalene-1,2-dione	IC50	2120 nM
5-(4,4-dimethyl-2-oxidanyl-6-oxidanylidene-cyclohexen-1-yl)-5-oxidanyl-1,3-diazinane-2,4,6-trione	IC50	2300 nM
MLS000541664	IC50	2500 nM
MLS000768248	IC50	2550 nM
cid_15945067	IC50	2820 nM
(1Z)-1-[(4-hydroxyanilino)methylidene]-2-naphthalenone	EC50	2840 nM
N-(2-hydroxy-1,3-dioxoinden-2-yl)-4-(trifluoromethyl)benzamide	IC50	2970 nM
4-morpholin-4-yl-2,1,3-benzoxadiazol-7-amine	IC50	2980 nM
2-Methyl-8-morpholin-4-yl-5,6-dioxo-5,6-dihydro-quinoline-4-carboxylic acid methyl ester	IC50	3210 nM
2,3-bis(2-furanyl)-N-(3-hydroxypropyl)-6-quinoxalinecarboxamide	IC50	3450 nM
4-[(5-methyl-1,2-oxazol-3-yl)amino]naphthalene-1,2-dione	IC50	3520 nM
2,5,8(1H)-Quinolinetrione, 6-hydroxy-	IC50	3800 nM
SMR000123743	IC50	3840 nM
7-chloro-4-nitro-N-(2-pyridinyl)-2,1,3-benzoxadiazol-5-amine	IC50	3980 nM
4-(3-pyridinylamino)naphthalene-1,2-dione	IC50	4030 nM
2-[2-[2-[[3-[(4-chlorophenyl)methoxy]-4-methoxy-phenyl]methylidene]hydrazinyl]-4-oxidanylidene-1,3-thiazol-5-yl]ethanoic acid	IC50	4960 nM
cid_2810379	IC50	5130 nM
2-[3-(3-methylbut-2-enyl)-1,4-dioxonaphthalen-2-yl]oxyacetic acid	IC50	6110 nM
3-(2-chloroanilino)-2H-isoquinolin-1-one	IC50	6110 nM
MLS000068755	IC50	6150 nM
MLS002701780	IC50	6810 nM
MLS000715646	IC50	7140 nM
(2-bromanyl-4,5-dimethoxy-phenyl)-(6,7-dimethoxyisoquinolin-1-yl)methanone	IC50	7370 nM
3-(2-pyridinylamino)-2H-isoquinolin-1-one	IC50	7380 nM
MLS000778447	IC50	7800 nM
SMR000156300	IC50	7830 nM
ethyl 4-methyl-6-[(5-nitrothiophene-2-carbonyl)oxymethyl]-2-oxo-3,4-dihydro-1H-pyrimidine-5-carboxylate	IC50	8130 nM
MLS000768249	IC50	8190 nM
[2-[(4-fluorophenyl)amino]-2-oxidanylidene-ethyl] 5-nitrothiophene-2-carboxylate	IC50	8430 nM
SMR001316144	IC50	8450 nM
cid_282415	IC50	8670 nM
methyl 2-[5-[bis(3-methyl-5-oxo-1,2-dihydropyrazol-4-yl)methyl]furan-2-yl]benzoate	IC50	8910 nM

ChEMBL bioactivities

266 potent at pChembl≥5 of 533 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.41	IC50	3.85	nM	CHEMBL5923878
8.30	IC50	5.01	nM	CHEMBL5821949
8.21	IC50	6.1	nM	CHEMBL4441013
8.21	IC50	6.09	nM	CHEMBL5815522
8.19	IC50	6.5	nM	CHEMBL4572376
8.19	IC50	6.49	nM	CHEMBL5942240
8.14	IC50	7.3	nM	CHEMBL4436202
8.14	IC50	7.25	nM	CHEMBL5943540
8.08	IC50	8.28	nM	CHEMBL6011555
7.87	IC50	13.6	nM	CHEMBL6008959
7.85	IC50	14	nM	CHEMBL4587441
7.70	IC50	20	nM	CHEMBL4520052
7.70	IC50	19.8	nM	CHEMBL5747346
7.52	EC50	30	nM	CHEMBL2420474
7.48	IC50	33	nM	CHEMBL4560735
7.48	IC50	33	nM	CHEMBL4468174
7.48	IC50	33.1	nM	CHEMBL5794235
7.48	IC50	32.8	nM	CHEMBL6032828
7.46	IC50	35	nM	CHEMBL4555612
7.46	IC50	35	nM	CHEMBL5875928
7.42	IC50	38	nM	CHEMBL4521151
7.42	IC50	38	nM	CHEMBL5963431
7.41	IC50	39	nM	CHEMBL5797270
7.40	EC50	40	nM	CHEMBL2420480
7.40	IC50	40	nM	CHEMBL4470500
7.39	IC50	41	nM	CHEMBL2420480
7.38	IC50	42	nM	CHEMBL2420507
7.33	IC50	47	nM	CHEMBL5913356
7.30	EC50	50	nM	CHEMBL2420507
7.30	EC50	50	nM	CHEMBL2420481
7.23	IC50	59	nM	CHEMBL5968903
7.19	IC50	65	nM	CHEMBL4457155
7.19	IC50	64.7	nM	CHEMBL5975468
7.16	IC50	70	nM	CHEMBL4546104
7.15	IC50	70.4	nM	CHEMBL5751691
7.05	EC50	90	nM	CHEMBL2420472
7.05	EC50	90	nM	CHEMBL2420465
6.92	EC50	120	nM	CHEMBL2420614
6.92	IC50	119	nM	CHEMBL5796252
6.92	IC50	119	nM	CHEMBL5976026
6.89	IC50	130	nM	CHEMBL4518508
6.88	IC50	131	nM	CHEMBL6050161
6.85	IC50	140	nM	CHEMBL2420465
6.82	EC50	150	nM	CHEMBL2420610
6.82	IC50	150	nM	CHEMBL4576353
6.82	IC50	153	nM	CHEMBL5764329
6.79	IC50	161.1	nM	CHEMBL1325945
6.73	IC50	186	nM	CHEMBL5756305
6.73	IC50	185	nM	CHEMBL6037182
6.72	IC50	190	nM	CHEMBL4557001

PubChem BioAssay actives

176 with measured affinity, of 652 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
N-[3-[3-(4-chlorophenyl)-8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl]phenyl]methanesulfonamide	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0061	uM
N-[4-[3-(4-chlorophenyl)-8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl]phenyl]methanesulfonamide	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0065	uM
3-(4-chlorophenyl)-10-(3-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0073	uM
3-(3,4-dichlorophenyl)-10-(3-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0140	uM
3-(3-chlorophenyl)-10-(3-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0200	uM
2,4-dioxo-10-[3-(tetrazol-1-yl)phenyl]-1,4a,5,5a,6,7,8,9,9a,10a-decahydropyrimido[4,5-b]quinoline-8-carbonitrile	1801792: TDP2 Assays with Whole Cell Extracts from Article 10.1021/acschembio.5b01047: “Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2.”	ic50	0.0250	uM
N-[3-(8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl)phenyl]methanesulfonamide	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.0300	uM
10-(4-hydroxyphenyl)-2,4-dioxo-3-phenylpyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0330	uM
3-(4-chlorophenyl)-10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0330	uM
3-[8-cyano-10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinolin-3-yl]benzamide	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0350	uM
methyl 3-[8-cyano-10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinolin-3-yl]benzoate	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0380	uM
7-amino-5-imino-1H-quinoline-2,8-dione	1574190: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0400	uM
2,4-dioxo-10-[3-(2H-tetrazol-5-yl)phenyl]pyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.0400	uM
10-(3-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0420	uM
3-[4-(3,4-dimethoxyphenyl)thiophen-2-yl]-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.0500	uM
10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1801792: TDP2 Assays with Whole Cell Extracts from Article 10.1021/acschembio.5b01047: “Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2.”	ic50	0.0620	uM
3-(4-bromophenyl)-10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0650	uM
3-(4-fluorophenyl)-10-(4-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.0700	uM
10-(3-aminophenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.0900	uM
1,6-dimethyl-3-(4-phenylthiophen-2-yl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.1200	uM
3-[[4-(8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl)phenoxy]methyl]benzoic acid	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.1300	uM
methyl 3-[[4-(8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl)phenoxy]methyl]benzoate	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.1500	uM
1,6-dimethyl-3-naphthalen-2-ylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.1500	uM
2,4-dioxo-10-phenylpyrimido[4,5-b]quinoline-8-carbonitrile	1801792: TDP2 Assays with Whole Cell Extracts from Article 10.1021/acschembio.5b01047: “Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2.”	ic50	0.1800	uM
3-[4-(8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl)phenoxy]benzoic acid	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.1900	uM
2,4-dioxo-10-(4-phenylmethoxyphenyl)pyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.2000	uM
3-(4-bromothiophen-2-yl)-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2000	uM
1,6-dimethyl-3-(4-methylthiophen-2-yl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2500	uM
10-[3-(hydroxymethyl)phenyl]-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2500	uM
1,6-dimethyl-3-[4-(trifluoromethoxy)phenyl]pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2600	uM
3-(4-chlorophenyl)-2,4-dioxo-10-phenylpyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.2700	uM
3-(4-ethylphenyl)-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2800	uM
3-(4-ethylphenyl)-6-methyl-1-propylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2800	uM
1,6-dimethyl-3-(4-methylphenyl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2900	uM
3-(8-cyano-2,4-dioxopyrimido[4,5-b]quinolin-10-yl)benzenesulfonamide	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.2900	uM
2,4-dioxo-10-(3-phenoxyphenyl)pyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.3000	uM
1-ethyl-3-(4-ethylphenyl)-6-methylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3000	uM
10-(4-hydroxyphenyl)-3-methyl-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.3200	uM
10-(3-hydroxy-4-methoxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3200	uM
1,6-dimethyl-3-[4-(trifluoromethyl)phenyl]pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3300	uM
1-(cyclopropylmethyl)-3-(4-ethylphenyl)-6-methylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3600	uM
3-cyclopropyl-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3700	uM
10-(1H-indazol-4-yl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.3700	uM
2,4-dioxo-10-(3-phenylmethoxyphenyl)pyrimido[4,5-b]quinoline-8-carbonitrile	1588023: Inhibition of humanized zebrafish TDP2 using 5’-(6-FAM-NHS) as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence assay	ic50	0.3800	uM
1,6-dimethyl-3-(3-methylphenyl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.4000	uM
3-(4-chlorophenyl)-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.4300	uM
1,6-dimethyl-3-(oxan-4-yl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.4300	uM
10-(3-methoxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.4700	uM
8-chloro-10-(3-hydroxyphenyl)pyrimido[4,5-b]quinoline-2,4-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.4800	uM
1,6-dimethyl-3-propylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	765294: Inhibition of TDP2 (unknown origin) using 4-nitrophenyl phenylphosphonate as substrate after 60 mins	ec50	0.5100	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation	2
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
lead acetate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cupric chloride	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzene	increases expression	1
Benzo(a)pyrene	increases expression	1
Cadmium	decreases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases response to substance, increases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Menthol	increases expression	1
Quercetin	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1
beta-Naphthoflavone	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

30 unique, capped per target: 30 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2174998	Binding	Inhibition of recombinant Tdp2	5-Arylidenethioxothiazolidinones as inhibitors of tyrosyl-DNA phosphodiesterase I. — J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2IB	Abcam HeLa TDP2 KO	Cancer cell line	Female
CVCL_E2LQ	HAP1 TDP2 (-) 2	Cancer cell line	Male
CVCL_F1KQ	DT40-TDP2(-/-/-) hTDP2	Cancer cell line	Female
CVCL_F1KR	DT40-TDP2(-/-/-) hTDP2 D262A	Cancer cell line	Female
CVCL_XU14	HAP1 TDP2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00863538	PHASE2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	PHASE2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT02540655	PHASE2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT03932669	PHASE2	COMPLETED	Effect of Nilotinib in Cerebellar Ataxia Patients
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05125666	PHASE2	UNKNOWN	Efficacy of Dual Task Training on Children With Ataxia After Medulloblastoma Resection
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT00683943	PHASE1	COMPLETED	Lithium Treatment for Patients With Spinocerebellar Ataxia Type I
NCT02287064	PHASE1	UNKNOWN	An Open-label Trial of Intravenous Immune Globulin (IVIG)in Treating Spinocerebellar Ataxias
NCT05157802	PHASE1	ACTIVE_NOT_RECRUITING	Promoting Physical Activity Engagement for People With Early-stage Cerebellar Ataxia
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01104649	PHASE2/PHASE3	COMPLETED	Efficacy of Riluzole in Hereditary Cerebellar Ataxia
NCT02960893	PHASE2/PHASE3	COMPLETED	Trial in Adult Participants With Spinocerebellar Ataxia (SCA)
NCT00244361	PHASE1/PHASE2	COMPLETED	Effectiveness of Rituximab in Pediatric OMS Patients.
NCT01649687	PHASE1/PHASE2	COMPLETED	Treatment of Cerebellar Ataxia With Mesenchymal Stem Cells
NCT01958177	PHASE1/PHASE2	UNKNOWN	Clinical Study to Evaluate the Safety and Efficacy BMMNC in Cerebellar Ataxia
NCT02829268	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
NCT00001324	Not specified	COMPLETED	PET Scan to Study Brain Control of Human Movement
NCT00006492	Not specified	COMPLETED	Gluten-Free Diet in Patients With Gluten Sensitivity and Cerebellar Ataxia
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00272272	Not specified	COMPLETED	Fall Prevention in a Geriatric Nursing Home Setting Using the Music of Nolwenn Leroy
NCT00654251	Not specified	COMPLETED	Measuring Neurological Impairment and Functional Visual Assessment In Spinocerebellar Ataxias
NCT00692861	Not specified	COMPLETED	Autoimmunity in Neurologic Complications of Celiac Disease
NCT01037777	Not specified	COMPLETED	RISCA : Prospective Study of Individuals at Risk for SCA1, SCA2, SCA3, SCA6, SCA7
NCT01307176	Not specified	COMPLETED	Exercise Training Program for Cerebellar Ataxia