POLQ

Summary

POLQ (DNA polymerase theta, HGNC:9186) is a protein-coding gene on chromosome 3q13.33, encoding DNA polymerase theta (O75417). Low-fidelity DNA polymerase with a putative helicase activity that promotes microhomology-mediated end-joining (MMEJ), an alternative non-homologous end-joining (NHEJ) machinery required to repair double-strand breaks in DNA during mitosis.

Enables several functions, including catalytic activity, acting on DNA; identical protein binding activity; and magnesium ion binding activity. Involved in DNA metabolic process; negative regulation of double-strand break repair via homologous recombination; and protein homooligomerization. Located in nucleoplasm. Is active in mitochondrial nucleoid; nucleus; and site of double-strand break.

Source: NCBI Gene 10721 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Clinical variants (ClinVar): 3,612 total (top 1% of genes corpus-wide)
• GTEx eGene: eQTL in 8 tissues, sQTL in 3 (q < 0.05)
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.03 (unconstrained)
• MANE Select transcript: NM_199420
• Notable: 3,612 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9186
Approved symbol	POLQ
Name	DNA polymerase theta
Location	3q13.33
Locus type	gene with protein product
Status	Approved
Aliases	POLH
Ensembl gene	ENSG00000051341
Ensembl biotype	protein_coding
OMIM	604419
Entrez	10721

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 6 protein_coding, 5 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000264233

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 3: 1, TSL 5: 1

ENST00000264233, ENST00000474243, ENST00000488282, ENST00000683498, ENST00000932951, ENST00000932952, ENST00000932953, ENST00001001856, ENST00001079430, ENST00001079431, ENST00001079432, ENST00001079433, ENST00001141192

RefSeq mRNA: 1 — MANE Select: NM_199420 NM_199420

CCDS: CCDS33833

Canonical transcript exons

ENST00000264233 — 30 exons

Exon	Start	End
ENSE00001012319	121436122	121436275
ENSE00001012327	121439992	121440116
ENSE00001012336	121432918	121433033
ENSE00001078698	121485041	121485184
ENSE00001078703	121460050	121460234
ENSE00001078706	121473350	121473487
ENSE00001078710	121481572	121481812
ENSE00001078711	121498477	121498670
ENSE00001078712	121471990	121472164
ENSE00001078713	121493478	121493721
ENSE00001078715	121487302	121490408
ENSE00001078718	121496808	121496932
ENSE00001078721	121509561	121509703
ENSE00001078722	121483386	121483582
ENSE00001149642	121511887	121512029
ENSE00001235285	121510039	121510243
ENSE00001235300	121519871	121520083
ENSE00001235330	121532990	121533209
ENSE00001235341	121537100	121537208
ENSE00001235348	121539433	121539589
ENSE00001235355	121541349	121541479
ENSE00001235361	121544727	121544906
ENSE00001235367	121545715	121545988
ENSE00001858247	121431431	121432417
ENSE00003503491	121476540	121476733
ENSE00003529215	121449315	121449426
ENSE00003640944	121529645	121529792
ENSE00003658205	121467519	121467640
ENSE00003668918	121522003	121522149
ENSE00003693250	121468305	121468431

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 87.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.3350 / max 274.0797, expressed in 982 samples.

Highest expression (Bgee): secondary oocyte, oocyte, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, esophagus squamous epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

POLQ is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 8 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

11 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Mucosa	eqtl	1.3e-05	+0.11	3:121466414:G:GGC
Esophagus Mucosa	sqtl	2.1e-04	-1.29	3:121174199:T:G
Cells EBV-transformed lymphocytes	eqtl	6.3e-04	-0.30	3:121404216:C:T
Testis	sqtl	5.3e-03	-1.38	3:121174199:T:G
Muscle Skeletal	eqtl	1.4e-02	-0.15	3:121576427:C:T
Artery Aorta	eqtl	1.9e-02	+0.39	3:121616610:C:T
Vagina	sqtl	2.0e-02	-2.84	3:122172161:G:T
Ovary	eqtl	2.0e-02	+0.42	3:120597356:G:C
Colon Transverse	eqtl	2.4e-02	+0.10	3:122323653:T:A
Brain Cortex	eqtl	3.7e-02	-0.26	3:121334600:G:T
Adipose Subcutaneous	eqtl	3.8e-02	-0.51	3:122270069:T:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
44093	3.9700	961
44094	0.2505	111
44092	0.1145	52

Top tissues by expression

showing 100 of 268 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	87.92	gold quality
oocyte	CL:0000023	82.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.10	gold quality
ventricular zone	UBERON:0003053	79.88	gold quality
esophagus squamous epithelium	UBERON:0006920	75.20	gold quality
bone marrow	UBERON:0002371	74.44	gold quality
ganglionic eminence	UBERON:0004023	73.45	gold quality
bone marrow cell	CL:0002092	73.25	gold quality
squamous epithelium	UBERON:0006914	73.04	gold quality
hair follicle	UBERON:0002073	72.45	gold quality
trabecular bone tissue	UBERON:0002483	72.19	gold quality
stromal cell of endometrium	CL:0002255	71.89	gold quality
epithelium of esophagus	UBERON:0001976	71.35	gold quality
embryo	UBERON:0000922	71.09	gold quality
mucosa of transverse colon	UBERON:0004991	70.98	gold quality
gingival epithelium	UBERON:0001949	70.94	silver quality
cervix squamous epithelium	UBERON:0006922	70.43	gold quality
esophagus mucosa	UBERON:0002469	69.46	gold quality
mucosa of paranasal sinus	UBERON:0005030	69.46	silver quality
lower esophagus mucosa	UBERON:0035834	69.37	gold quality
rectum	UBERON:0001052	69.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.99	gold quality
vermiform appendix	UBERON:0001154	67.40	gold quality
adrenal tissue	UBERON:0018303	67.38	gold quality
diaphragm	UBERON:0001103	65.95	gold quality
tibia	UBERON:0000979	65.70	silver quality
epithelium of bronchus	UBERON:0002031	65.04	gold quality
ileal mucosa	UBERON:0000331	64.76	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	64.45	gold quality
bronchial epithelial cell	CL:0002328	64.34	gold quality
bronchus	UBERON:0002185	64.16	gold quality
buccal mucosa cell	CL:0002336	63.85	gold quality
caecum	UBERON:0001153	63.63	gold quality
oral cavity	UBERON:0000167	63.59	silver quality
lymph node	UBERON:0000029	63.27	gold quality
amniotic fluid	UBERON:0000173	63.16	silver quality
colonic epithelium	UBERON:0000397	62.87	gold quality
duodenum	UBERON:0002114	61.90	gold quality
thymus	UBERON:0002370	61.61	silver quality
tonsil	UBERON:0002372	61.20	gold quality
nasal cavity epithelium	UBERON:0005384	61.11	silver quality
cervix epithelium	UBERON:0004801	60.76	gold quality
endometrium	UBERON:0001295	60.60	gold quality
pancreatic ductal cell	CL:0002079	59.89	silver quality
cardiac muscle of right atrium	UBERON:0003379	59.76	gold quality
left ventricle myocardium	UBERON:0006566	59.43	gold quality
placenta	UBERON:0001987	59.26	gold quality
upper leg skin	UBERON:0004262	59.21	silver quality
tibialis anterior	UBERON:0001385	59.16	silver quality
testis	UBERON:0000473	59.05	gold quality
right testis	UBERON:0004534	58.12	gold quality
transverse colon	UBERON:0001157	58.07	gold quality
tongue squamous epithelium	UBERON:0006919	57.95	gold quality
germinal epithelium of ovary	UBERON:0001304	57.91	gold quality
endothelial cell	CL:0000115	57.86	gold quality
decidua	UBERON:0002450	57.45	gold quality
left testis	UBERON:0004533	57.42	gold quality
nasopharynx	UBERON:0001728	57.12	silver quality
epithelium of nasopharynx	UBERON:0001951	57.12	silver quality
spleen	UBERON:0002106	56.92	gold quality
smooth muscle tissue	UBERON:0001135	56.91	gold quality
cranial nerve II	UBERON:0000941	56.67	silver quality
mucosa of sigmoid colon	UBERON:0004993	56.48	silver quality
nasal cavity mucosa	UBERON:0001826	56.38	gold quality
colonic mucosa	UBERON:0000317	56.34	gold quality
superficial temporal artery	UBERON:0001614	56.33	gold quality
small intestine	UBERON:0002108	56.32	gold quality
esophagus	UBERON:0001043	56.30	gold quality
cartilage tissue	UBERON:0002418	56.12	silver quality
skin of hip	UBERON:0001554	56.10	silver quality
small intestine Peyer’s patch	UBERON:0003454	55.61	gold quality
mucosa of urinary bladder	UBERON:0001259	55.44	gold quality
pharyngeal mucosa	UBERON:0000355	55.02	silver quality
myocardium	UBERON:0002349	55.00	gold quality
right adrenal gland cortex	UBERON:0035827	54.97	gold quality
right adrenal gland	UBERON:0001233	54.67	gold quality
jejunal mucosa	UBERON:0000399	54.60	gold quality
visceral pleura	UBERON:0002401	54.48	gold quality
intestine	UBERON:0000160	54.18	gold quality
pleura	UBERON:0000977	53.59	silver quality
vagina	UBERON:0000996	53.28	gold quality
large intestine	UBERON:0000059	53.02	gold quality
skin of abdomen	UBERON:0001416	52.76	gold quality
colon	UBERON:0001155	52.75	gold quality
muscle tissue	UBERON:0002385	52.46	gold quality
zone of skin	UBERON:0000014	51.67	gold quality
deltoid	UBERON:0001476	51.67	gold quality
adrenal gland	UBERON:0002369	51.58	gold quality
skin of leg	UBERON:0001511	51.53	gold quality
uterus	UBERON:0000995	51.46	gold quality
epithelial cell of pancreas	CL:0000083	51.18	gold quality
cardiac atrium	UBERON:0002081	51.12	gold quality
islet of Langerhans	UBERON:0000006	50.85	gold quality
quadriceps femoris	UBERON:0001377	50.68	gold quality
uterine cervix	UBERON:0000002	50.57	gold quality
right atrium auricular region	UBERON:0006631	50.52	gold quality
left adrenal gland	UBERON:0001234	50.50	gold quality
female reproductive system	UBERON:0000474	50.34	gold quality
adrenal cortex	UBERON:0001235	50.25	gold quality
liver	UBERON:0002107	50.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.47
E-GEOD-81383	no	172.91

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 64 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Bone marrow	tissue	5.6
Thymus	tissue	4.2
Cerebellum	tissue	3.5
Lymph node	tissue	2.6
Tonsil	tissue	2.2
Testis	tissue	2.0
Rectum	tissue	1.9
Postcentral gyrus	tissue	1.9
Appendix	tissue	1.5
Skin 1	tissue	1.3
Colon	tissue	1.2
Duodenum	tissue	1.1
Placenta	tissue	1.0
Esophagus	tissue	0.9
Putamen	tissue	0.9
Small intestine	tissue	0.9
Hippocampus	tissue	0.9
Hippocampal formation	tissue	0.9
Basal ganglia	tissue	0.8
Cerebral cortex	tissue	0.7
Nucleus accumbens	tissue	0.7
Retrosplenial and cingulate cortex	tissue	0.7
Olfactory bulb	tissue	0.7
Motor cortex	tissue	0.6
Ventral forebrain	tissue	0.6
Retrosplenial cortex	tissue	0.6
Temporal cortex	tissue	0.6
Occipital cortex	tissue	0.6
Insular cortex	tissue	0.6
Prefrontal cortex	tissue	0.5
Stomach 1	tissue	0.5
Vagina	tissue	0.5
Amygdala	tissue	0.5
Entorhinal cortex	tissue	0.5
Somatosensory cortex	tissue	0.5
Breast	tissue	0.4
Spleen	tissue	0.4
Septum	tissue	0.4
Smooth muscle	tissue	0.3
Urinary bladder	tissue	0.3
Choroid plexus	tissue	0.3
Midbrain	tissue	0.3
Hypothalamus	tissue	0.3
Locus coeruleus	tissue	0.3
Corpus callosum	tissue	0.3
Periaqueductal gray	tissue	0.3
Pons	tissue	0.2
Endometrium 1	tissue	0.2
Medulla oblongata	tissue	0.2
Thalamus	tissue	0.2
Substantia nigra	tissue	0.2
Spinal cord	tissue	0.2
Cervix	tissue	0.1
Heart muscle	tissue	0.1
Ovary	tissue	0.1
Adipose tissue	tissue	0.1
Parathyroid gland	tissue	0.1
Frontal cortex	tissue	0.1
Superior colliculi	tissue	0.1
Lung	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Vermis (3.5), Flocculonodular lobe (3.0), Cerebellar cortex (2.9), Parietal operculum (1.8), Parieto-insular cortex (1.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting POLQ by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 101 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-545-3P	99.95	70.74	2783

Functional genomics

gnomAD constraint: pLI 1.83e-46, LOEUF 1.03, missense Z 1.64 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000264233 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:121,432,307–121,493,706	2080 / 2126.0	0.98	no
3:121,493,707–121,496,843	8 / 19.3	0.41	no
3:121,496,844–121,545,877	783 / 906.2	0.86	no

Literature-anchored findings (GeneRIF, showing 40)

• DNA polymerase theta purified from human cells is a high-fidelity enzyme. (PMID:12051913)
• the isolation of the full-length human DNA POLQ gene, and an initial characterization of its gene product, DNA polymerase theta (PMID:14576298)
• DNA Pol theta has a specialized function in lymphocytes and in tumor progression (PMID:14735462)
• POLQ has a high efficiency in by-passing DNA damage. (PMID:15496986)
• analysis of human DNA polymerase eta error-prone synthesis on DNA deoxyadenosine adducts (PMID:16188888)
• The results demonstrate that activation of a UV-induced DNA damage response pathway, involving phosphorylation of RPA p34 by DNA-PK, is enhanced in cells lacking poleta. (PMID:16520097)
• Pol eta can play an important role in determining the cellular sensitivity to therapeutic agents. (PMID:16603639)
• DNA polymerase eta (Poleta) is responsible for efficient translesion synthesis (TLS) past cis-syn cyclobutane thymine dimers (TT dimers), the major DNA lesions induced by UV irradiation. (PMID:16824193)
• Human DNA polymerase eta selectively produces a two-base deletion in copying the N2-guanyl adduct of 2-amino-3-methylimidazo[4,5-f]quinoline but not the C8 adduct at the NarI G3 site (PMID:16835218)
• The enzymatic reactions with human DNA polymerase eta on oxidative products of guanine and 8-oxoG, is investigated. (PMID:17150533)
• Evolutionary conservation of efficient T[CPD]T bypass by HsPoleta and AtPoleta may reflect a high degree of exposure of human skin and plants to solar UV-B radiation (PMID:18366182)
• When copying undamaged DNA, DNA polymerase theta generates single base errors at rates 10- to more than 100-fold higher than for other family A members. (PMID:18503084)
• Domain mapping of the 98-kDa enzyme by limited proteolysis and NaBH(4) cross-linking with a base excision repair intermediate revealed that the dRP lyase active site resides in a 24-kDa domain of Pol theta. (PMID:19188258)
• Data show that POLQ overexpression may be a promising genetic instability and prognostic marker for breast cancer. (PMID:20624954)
• overexpression in breast cancer confers an adverse prognosis and is associated with key cancer pathways (PMID:20700469)
• POLQ possesses a DNA polymerase activity that appears to be template independent and allows efficient extension of single-stranded DNA as well as duplex DNA with either protruding or multiply mismatched 3’-OH termini. (PMID:22135286)
• Use fluorescence resonance energy transfer to monitor assembly of the human replicative polymerase holoenzyme. (PMID:23577232)
• A role for DNA polymerase theta; in promoting replication through oxidative DNA lesion, thymine glycol, in human cells. (PMID:24648516)
• A DNA repair variant in POLQ (c.-1060A > G) is associated to hereditary breast cancer patients. (PMID:25409685)
• These results suggest that variants in the POLQ gene may be associated with the risk of Luminal breast cancer (PMID:25417172)
• depletion of Poltheta; has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes (PMID:25642960)
• results reveal a synthetic lethal relationship between the homologous-recombination pathway and Poltheta;-mediated repair in epithelial ovarian cancers, and identify Poltheta; as a novel druggable target for cancer therapy (PMID:25642963)
• Microhomology-mediated end-joining is dependent on Poltheta; in human cells. (PMID:25643323)
• Polymerase theta; uses a specialized thumb subdomain to establish unique upstream contacts to the primer DNA strand. (PMID:25775267)
• Our results indicate that there is a synthetic lethal relationship between pol theta;-mediated DNA repair and homologous recombination pathways (PMID:27533083)
• This article summarizes work on the expression and purification of the full-length protein, and then focus on the design, expression, and purification of an active C-terminal polymerase fragment. Strategies to obtain and improve crystals of a ternary POLQ complex (enzyme:DNA:nucleotide) are also presented, along with key elements of the structure. (PMID:28668117)
• Cells doubly deficient in Pol theta; and Lig4 exhibit 100% gene-targeting efficiency because of virtually no random integration events. (PMID:28695890)
• Data suggest that error-free DNA replication through 3-deaza-3-methyladenine adduct is mediated via three different pathways dependent upon POL-iota/POL-kappa, POL-theta, and POL-zeta. (PMID:28939775)
• results suggest that bypass of Tg by Pol theta; results in mutations opposite the lesion, as well as frameshift mutations (PMID:29243925)
• Data suggest that translesion DNA synthesis mediated by (1) POLI-dependent pathway (2) REV1- and POLN-dependent pathway, or (3) POLtheta-dependent pathway occur in predominantly error-free manner in human cells. (POLI = DNA polymerase iota; REV1 = DNA repair protein-REV1; POLN = DNA polymerase nu; POLtheta = DNA polymerase theta) (PMID:29330301)
• Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLtheta; pathways to hijack stalled replication forks, which the authors find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. (PMID:29334356)
• Heightened Poltheta; expression levels were also associated with elevated mtDNA mutation rates in a selected panel of human tumor tissues, suggesting that this protein can influence mutational frequencies in tumors. T (PMID:29509408)
• Based on previous studies and gene ontology database, we found that POLQ encoding DNA polymerase theta enzyme and FNIP1 encoding tumor suppressor folliculin-interacting protein might have contributed to the Interdigitating dendritic cell sarcoma (IDCS). Our study provides potential causative genetic factors of IDCS and plays a role in advancing the understanding of IDCS pathogenesis (PMID:30099721)
• Expanded Substrate Scope of DNA Polymerase theta; and DNA Polymerase beta: Lyase Activity on 5’-Overhangs and Clustered Lesions. (PMID:30299084)
• Rev1 polymerase and Poltheta; conduct translesion synthesis opposite 1,N(6)-ethenodeoxyadenosine via alternative error-prone pathways (PMID:30808656)
• Poltheta; shows a strong preference for adding deoxyribonucleotides to RNA, but can also add ribonucleotides with relatively high efficiency in particular sequence contexts; this unique activity of Poltheta; will become invaluable for applications requiring 3’ terminal modification of RNA and potentially enzymatic synthesis of RNA (PMID:30818397)
• RAD52 and POLQ are both synthetic lethal with loss of the BRCA1 and BRCA2 tumor suppressor genes. Furthermore, RAD52 and POLQ have been implicated in chromosomal break repair events that use flanking repeats to restore the chromosome. Combined disruption of RAD52 and POLQ causes at least additive hypersensitivity to cisplatin and a synthetic reduction in replication fork restart velocity. (PMID:31381562)
• The roles of polymerases nu and theta in replicative bypass of O (6)- and N (2)-alkyl-2’-deoxyguanosine lesions in human cells. (PMID:32098870)
• Genetic evidence for reconfiguration of DNA polymerase theta active site for error-free translesion synthesis in human cells. (PMID:32169903)
• DNA polymerase theta (Poltheta) - an error-prone polymerase necessary for genome stability. (PMID:32302896)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	polq	ENSDARG00000044622
mus_musculus	Polq	ENSMUSG00000034206
rattus_norvegicus	Polq	ENSRNOG00000002471
drosophila_melanogaster	PolQ	FBGN0002905
caenorhabditis_elegans		WBGENE00020964

Paralogs (8): MTREX (ENSG00000039123), ASCC3 (ENSG00000112249), DDX60 (ENSG00000137628), SNRNP200 (ENSG00000144028), HFM1 (ENSG00000162669), HELQ (ENSG00000163312), DDX60L (ENSG00000181381), SKIC2 (ENSG00000204351)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2155399) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 10 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal somatic hypermutation frequency	3
abnormal spleen morphology	1
small spleen	1
decreased IgG level	1
decreased IgM level	1
abnormal B cell physiology	1
decreased immunoglobulin level	1
chromosome breakage	1
decreased IgG1 level	1
increased grip strength	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Lactococcus cremoris subsp. cremoris MG1363	O32801	94.2%	Diamond
Methanocella arvoryzae MRE50	Q0W6L1	54.8%	Diamond
Saccharomyces cerevisiae S288C	P35207	51.0%	Diamond
Thermococcus kodakarensis KOD1	Q5JGV6	48.3%	Diamond
Dictyostelium discoideum	Q54XN7	43.6%	Diamond
Arabidopsis thaliana	F4JAA5	43.5%	Diamond
Schizosaccharomyces pombe 972h-	Q9P7T8	43.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR5682	ncRNA	100847043
STXBP5L	protein-coding	9515
ARGFX	protein-coding	503582
HCLS1	protein-coding	3059
FBXO40	protein-coding	51725
LINC02049	ncRNA	101926983

Protein

Protein identifiers

DNA polymerase theta — O75417 (reviewed: O75417)

Alternative names: DNA polymerase eta

All UniProt accessions (2): A0A804HJJ9, O75417

UniProt curated annotations — full annotation on UniProt →

Function. Low-fidelity DNA polymerase with a putative helicase activity that promotes microhomology-mediated end-joining (MMEJ), an alternative non-homologous end-joining (NHEJ) machinery required to repair double-strand breaks in DNA during mitosis. MMEJ is an error-prone repair pathway that produces deletions of sequences from the strand being repaired and promotes genomic rearrangements, such as telomere fusions, some of them leading to cellular transformation. MMEJ is required during mitosis to repair persistent double-strand breaks that originate in S-phase. Although error-prone, MMEJ protects against chromosomal instability and tumorigenesis. The polymerase acts by binding directly the 2 ends of resected double-strand breaks, allowing microhomologous sequences in the overhangs to form base pairs. It then extends each strand from the base-paired region using the opposing overhang as a template. Requires partially resected DNA containing 2 to 6 base pairs of microhomology to perform MMEJ. The polymerase lacks proofreading activity and is highly promiscuous: unlike most polymerases, promotes extension of ssDNA and partial ssDNA (pssDNA) substrates. When the ends of a break do not contain terminal microhomology must identify embedded complementary sequences through a scanning step. Promotes dissociation of the replication protein A complex (RPA/RP-A), composed of RPA1, RPA2 and RPA3, from resected double-strand breaks to allow their annealing and subsequent joining by MMEJ. Removal of RPA/RP-A complex proteins prevents RAD51 accumulation at resected ends, thereby inhibiting homology-recombination repair (HR) pathway. Also shows RNA-directed DNA polymerase activity to mediate DNA repair in vitro; however this activity needs additional evidence in vivo. May also have lyase activity. Involved in somatic hypermutation of immunoglobulin genes, a process that requires the activity of DNA polymerases to ultimately introduce mutations at both A/T and C/G base pairs. POLQ-mediated end joining activity is involved in random integration of exogenous DNA hampers. DNA helicase activity has been examined and has and has not been demonstrated.

Subunit / interactions. Homomultimer; forms homodimers and homotetramers. Interacts with RAD51. Interacts with ORC2 and ORC4. Interacts with RHNO1; interaction takes place during mitosis and promotes POLQ recruitment to DNA damage sites. Interacts (when phosphorylated) with TOPBP1 (via BRCT domains 7 and 8); promoting POLQ recruitment to DNA damage sites.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Highly expressed in testis.

Post-translational modifications. Phosphorylated by PLK1; promoting interaction with TOPBP1 and recruitment to DNA damage sites.

Disease relevance. Breast cancer (BC) [MIM:114480] A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. The gene represented in this entry may be involved in disease pathogenesis.

Activity regulation. Specifically inhibited by the antibiotic novobiocin. The polymerase activity is specifically inhibited by the small molecule ART558. Novobiocin and ART558 confer specific killing of BRCA1/2-deficient cells and synergize with the poly [ADP-ribose] polymerase (PARP) inhibitor olaparib.

Domain organisation. The N-terminal helicase-like domain (residues 1-894) unwinds DNA with 3’-5’ polarity on substrates with 3’ and 5’ overhangs, blunt ends and replication forks. It also unwinds RNA:DNA hybrids with a 3’ DNA overhang; it does not translocate on RNA and does not unwind RNA:RNA hybrids. The loop 2 region is involved in the binding of the 2 ends of resected double-strand breaks and homomultimerization.

Similarity. Belongs to the DNA polymerase type-A family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75417-1	1	yes
O75417-2	2

RefSeq proteins (1): NP_955452* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001098	DNA-dir_DNA_pol_A_palm_dom	Domain
IPR001650	Helicase_C-like	Domain
IPR002298	DNA_polymerase_A	Family
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR014001	Helicase_ATP-bd	Domain
IPR019760	DNA-dir_DNA_pol_A_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036397	RNaseH_sf	Homologous_superfamily
IPR043502	DNA/RNA_pol_sf	Homologous_superfamily
IPR046931	HTH_61	Domain
IPR048960	POLQ-like_helical	Domain
IPR057220	DUF7898	Domain

Pfam: PF00270, PF00271, PF00476, PF20470, PF21099, PF25453

Catalyzed reactions (Rhea)

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)
• DNA(n) + a 2’-deoxyribonucleoside 5’-triphosphate = DNA(n+1) + diphosphate (RHEA:22508)

UniProt features (215 total): helix 91, strand 60, turn 14, modified residue 11, region of interest 10, mutagenesis site 8, binding site 5, sequence conflict 5, compositionally biased region 4, domain 2, splice variant 2, chain 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

showing 30 of 33 structures by resolution:

PDB	Title	Method	Resolution (Å)
9YSI	Covalent allosteric inhibitor of human DNA polymerase theta	X-RAY DIFFRACTION	2
7ZUS	Crystal structure of ternary complex of Pol theta polymerase domain	X-RAY DIFFRACTION	2.26
8E24	Human DNA polymerase theta in complex with allosteric inhibitor	X-RAY DIFFRACTION	2.34
9D6N	Loop-Deleted DNA Polymerase Theta in Complex with a dsDNA Overhang and an Allostertic …	X-RAY DIFFRACTION	2.43
8E23	Human DNA polymerase theta in complex with allosteric inhibitor	X-RAY DIFFRACTION	2.59
9OSW	Tetrameric POLQ Helicase-like Domain Bound to Cmpd 19, a Small-Molecule ATPase Inhibitor …	ELECTRON MICROSCOPY	2.67
9YSH	Allosteric inhibitor of human DNA polymerase theta	X-RAY DIFFRACTION	2.71
7ZX1	Crystal structure of Pol theta polymerase domain in complex with compound 22	X-RAY DIFFRACTION	2.83
5AGA	Crystal structure of the Helicase domain of human DNA polymerase theta in complex with …	X-RAY DIFFRACTION	2.9
9OSY	Tetrameric POLQ Helicase-like Domain Bound to Cmpd 36, a Small-Molecule ATPase Inhibitor …	ELECTRON MICROSCOPY	2.9
7ZX0	Crystal structure of Pol theta polymerase domain in complex with compound 5	X-RAY DIFFRACTION	2.99
9C5Q	Human DNA polymerase theta helicase domain in microhomology annealed state 2, dimer form	ELECTRON MICROSCOPY	3.1
9AU5	Ternary complex of human DNA polymerase theta polymerase domain with a cognate C:G base …	ELECTRON MICROSCOPY	3.11
5A9F	Crystal structure of the Helicase domain of human DNA polymerase theta in complex with ADP	X-RAY DIFFRACTION	3.2
8W0A	Human DNA polymerase theta helicase domain in complex with ssDNA, dimer form	ELECTRON MICROSCOPY	3.2
9BP9	Human DNA polymerase theta helicase domain in complex with inhibitor AB25583, dimer form	ELECTRON MICROSCOPY	3.21
9BPA	Human DNA polymerase theta helicase domain in complex with inhibitor AB25583, tetramer …	ELECTRON MICROSCOPY	3.21
8GD7	Loop Deleted DNA Polymerase Theta Polymerase Domain in Complex with Double Strand DNA …	X-RAY DIFFRACTION	3.24
6XBU	polymerase domain of polymerase-theta	X-RAY DIFFRACTION	3.29
9BH6	Human DNA polymerase theta helicase domain tetramer in the apo form	ELECTRON MICROSCOPY	3.3
9D6O	Loop-Deleted DNA Polymerase Theta Polymerase Domain in Complex with a dsDNA Overhang and …	X-RAY DIFFRACTION	3.31
9AU9	Ternary complex of human DNA polymerase theta polymerase domain with a mismatched T:G …	ELECTRON MICROSCOPY	3.32
9AU8	Ternary complex of human DNA polymerase theta polymerase domain with a mismatched T:T …	ELECTRON MICROSCOPY	3.44
9ASJ	Human DNA polymerase theta helicase domain in complex with AMP-PNP, dimer form	ELECTRON MICROSCOPY	3.5
9ASL	Human DNA polymerase theta helicase domain tetramer, apo-form	ELECTRON MICROSCOPY	3.5
9BH7	Human DNA polymerase theta helicase domain dimer in the apo form	ELECTRON MICROSCOPY	3.5
9BH9	Human DNA polymerase theta helicase domain dimer bound to DNA in the microhomology …	ELECTRON MICROSCOPY	3.5
9BHA	Human DNA polymerase theta helicase domain dimer bound to DNA in the microhomology …	ELECTRON MICROSCOPY	3.5
5A9J	Crystal structure of the Helicase domain of human DNA polymerase theta, apo-form	X-RAY DIFFRACTION	3.55
9ASK	Human DNA polymerase theta helicase domain dimer, apo-form	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75417-F1	59.68	0.13

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Cancer-related genes, Disease related genes, Potential drug targets

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol; golgi apparatus

Antibody reliability (HPA): IF supported

Functional residue map

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

Ligand- & substrate-binding residues (5)

Position	Role
96	ATP
115–122	ATP
2330	Mg(2+)
2331	Mg(2+)
2540	Mg(2+)

Post-translational modifications (11)

Type	Positions
N6-acetyllysine	990
Phosphoserine	1289, 1482, 1486, 1488, 1493, 1555, 1563, 1628, 1635
Phosphothreonine	1755

Mutagenesis-validated functional residues (8)

Position	Phenotype
121	loss of dna helicase activity. abolished atpase activity.
1482–1493	in 4s-p mutant; decreased phosphorylation by plk1, leading to impaired interaction with topbp1 and recruitment to dna damage sites.
1977	decreased protein stability.
2181	impaired ability to bypass abasic sites.
2202	impaired ability to bypass abasic sites. in pol-theta(rr) mutant; abolished polymerase activity; when associated with v-2254.
2254	impaired ability to bypass abasic sites.
2254	in pol-theta(rr) mutant; abolished polymerase activity; when associated with a-2202.
2540–2541	abolishes dna polymerase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-5685939	HDR through MMEJ (alt-NHEJ)	curated
R-HSA-5693532	DNA Double-Strand Break Repair	—
R-HSA-73894	DNA Repair	—
R-HSA-5693538	Homology Directed Repair	—

MSigDB gene sets: 423 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_UV_C, GOBP_REGULATION_OF_DNA_RECOMBINATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, WANG_CLIM2_TARGETS_UP, KANG_DOXORUBICIN_RESISTANCE_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_CELLULAR_RESPONSE_TO_UV, TGCACTT_MIR519C_MIR519B_MIR519A, CMYB_01, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_DNA_REPAIR, CGGAARNGGCNG_UNKNOWN

GO Biological Process (13): DNA repair (GO:0006281), base-excision repair (GO:0006284), double-strand break repair (GO:0006302), DNA damage response (GO:0006974), somatic hypermutation of immunoglobulin genes (GO:0016446), replication fork processing (GO:0031297), error-prone translesion synthesis (GO:0042276), protein homooligomerization (GO:0051260), double-strand break repair via alternative nonhomologous end joining (GO:0097681), negative regulation of double-strand break repair via homologous recombination (GO:2000042), DNA replication (GO:0006260), DNA-templated DNA replication (GO:0006261), RNA-templated DNA biosynthetic process (GO:0006278)

GO Molecular Function (21): magnesium ion binding (GO:0000287), DNA helicase activity (GO:0003678), chromatin binding (GO:0003682), damaged DNA binding (GO:0003684), DNA-directed DNA polymerase activity (GO:0003887), RNA-directed DNA polymerase activity (GO:0003964), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), single-stranded DNA helicase activity (GO:0017116), identical protein binding (GO:0042802), 5’-deoxyribose-5-phosphate lyase activity (GO:0051575), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), catalytic activity (GO:0003824), helicase activity (GO:0004386), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), hydrolase activity (GO:0016787), DNA polymerase activity (GO:0034061)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), site of double-strand break (GO:0035861), mitochondrial nucleoid (GO:0042645), site of DNA damage (GO:0090734), chromosome (GO:0005694)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Homology Directed Repair	1
DNA Repair	1
DNA Double-Strand Break Repair	1

GO top-level categories

49 GO namespaces:

Category	Terms
binding	3
DNA metabolic process	2
DNA repair	2
DNA biosynthetic process	2
DNA polymerase activity	2
ATP-dependent activity	2
catalytic activity	2
cellular anatomical structure	2
intracellular membraneless organelle	2
DNA damage response	1
cellular response to stress	1
somatic diversification of immune receptors via somatic mutation	1
somatic diversification of immunoglobulins	1
DNA-templated DNA replication maintenance of fidelity	1
translesion synthesis	1
protein complex oligomerization	1
double-strand break repair via nonhomologous end joining	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
negative regulation of DNA recombination	1
negative regulation of double-strand break repair	1
DNA replication	1
metal ion binding	1
helicase activity	1
ATP-dependent activity, acting on DNA	1
DNA binding	1
RNA-templated DNA biosynthetic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
ribonucleoside triphosphate phosphatase activity	1
DNA helicase activity	1
protein binding	1
carbon-oxygen lyase activity	1
catalytic activity, acting on DNA	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
molecular_function	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
transferase activity, transferring phosphorus-containing groups	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
site of DNA damage	1
mitochondrion	1
mitochondrial matrix	1
nucleoid	1
chromosome	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 20 of 40 annotations. The rest are phylogenetic / computational / electronic (IEA).

20 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response	BP	direct assay
base-excision repair	BP	direct assay
double-strand break repair	BP	direct assay
double-strand break repair via alternative nonhomologous end joining	BP	direct assay
error-prone translesion synthesis	BP	direct assay
negative regulation of double-strand break repair via homologous recombination	BP	direct assay
protein homooligomerization	BP	direct assay
replication fork processing	BP	direct assay
mitochondrial nucleoid	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
site of DNA damage	CC	direct assay
site of double-strand break	CC	direct assay
5’-deoxyribose-5-phosphate lyase activity	MF	direct assay
DNA helicase activity	MF	direct assay
DNA-directed DNA polymerase activity	MF	direct assay
chromatin binding	MF	direct assay
identical protein binding	MF	physical interaction
magnesium ion binding	MF	direct assay
single-stranded DNA helicase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,176 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLQ	UNG	P13051	825
POLQ	POLG	P54098	800
POLQ	GOLGB1	Q14789	759
POLQ	LIG4	P49917	722
POLQ	PARP1	P09874	660
POLQ	XRCC6	P12956	656
POLQ	XRCC5	P13010	656
POLQ	LIG3	P49916	636
POLQ	LIG1	P18858	631
POLQ	RBBP8	Q99708	628
POLQ	SHLD2	Q86V20	609
POLQ	REV3L	O60673	607
POLQ	BRCA2	P51587	596
POLQ	BRCA1	P38398	589
POLQ	EXO1	Q9UQ84	586

IntAct

Human interaction partners of POLQ in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
RBM25	physical association	0.560	1
TCERG1	association	0.350	1

BioGRID (31 interactions; top human partners by supporting records): RBM25 (Affinity Capture-MS; 2 records), AGO2 (Affinity Capture-RNA), AP2S1 (Affinity Capture-MS), BRCA2 (Negative Genetic), DCAF15 (Proximity Label-MS), DCAF16 (Proximity Label-MS), DCAF7 (Proximity Label-MS), DNAJA3 (Affinity Capture-MS), HEXIM1 (Affinity Capture-MS), HMGB1 (Cross-Linking-MS (XL-MS)), HSPA4 (Affinity Capture-MS), KIAA1429 (Affinity Capture-RNA), MAGEA9 (Affinity Capture-MS), MRE11A (Affinity Capture-Western), NCL (Cross-Linking-MS (XL-MS))

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
MDM2	“down-regulates quantity by destabilization”	POLQ	polyubiquitination
MDM2	“down-regulates quantity by destabilization”	POLQ	ubiquitination

Disease & clinical

Genetic variants

Variant evidence for POLQ: 3,612 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

3,612 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2394
Likely benign	1137
Benign	42

AlphaMissense

3,643 missense substitutions predicted likely pathogenic (of 17,093 scored), across 988 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M477	9	0.823	0.959
D216	8	0.977	0.992
H417	8	0.953	0.984
D2540	8	0.952	0.993
F765	8	0.951	0.993
F146	8	0.943	0.997
D2345	8	0.939	0.978
F2359	8	0.937	0.990
H416	8	0.935	0.991
F343	8	0.931	0.986
F432	8	0.923	0.991
D2330	8	0.919	0.970
D1988	8	0.914	0.970
H2539	8	0.910	0.949
F719	8	0.909	0.992
D2479	8	0.907	0.976
F2318	8	0.905	0.984
F2416	8	0.901	0.988
D647	8	0.897	0.978
D1829	8	0.890	0.929

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	unfavorable	4.16e-05
Lung Adenocarcinoma (TCGA)	unfavorable	0.000258
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000386

Disease associations

OMIM: gene MIM:604419 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6025 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 11,500 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL36506	NOVOBIOCIN	4	11,500

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — DNA polymerases

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
RP-2119	Inhibition	9.15	pIC50
SY-589	Inhibition	8.64	pIC50
RP-6685	Inhibition	8.24	pIC50
ART812	Inhibition	8.12	pIC50
ART558	Inhibition	8.1	pIC50

Binding affinities (BindingDB)

672 measured of 1072 human assays (2083 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[5-chloro-2-(difluoromethyl)-4-pyridinyl]-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-6-(4-methyl-6-oxopyridazin-1-yl)pyridine-3-carboxamide	IC50	0.049 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
CHEMBL5204203	IC50	0.068 nM
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(3-methyl-2-oxopyrazin-1-yl)pyridine-3-carboxamide	IC50	0.1 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3-thiazol-2-yl]-2-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-4-[2-(3-hydroxy-3-methylazetidin-1-yl)-2-oxoethyl]benzamide	IC50	0.16 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
CHEMBL5175156	IC50	0.2 nM
N-[5-[2-(4-cyanophenyl)cyclopropyl]-1,3,4-thiadiazol-2-yl]-5-[2-methoxy-5-(trifluoromethyl)phenyl]-1-[2-(methylamino)-2-oxoethyl]-2-oxopyridine-4-carboxamide	IC50	0.25 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(3-morpholin-4-ylprop-1-ynyl)pyridine-3-carboxamide	IC50	0.25 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(8-oxo-7-azaspiro[3.5]nonan-7-yl)pyridine-3-carboxamide	IC50	0.25 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-2-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-4-(1,2-dimethylimidazol-4-yl)benzamide	IC50	0.25 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(1-oxo-3,4,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl)pyridine-3-carboxamide	IC50	0.25 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
1-(2-amino-2-oxoethyl)-5-(2-chloro-5-methoxy-4-pyridinyl)-2-oxo-N-[5-(2-spiro[2.2]pentan-2-ylethynyl)-1,3,4-thiadiazol-2-yl]pyridine-4-carboxamide	IC50	0.26 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
ethanimidoyl 2-[5-[2-chloro-5-(difluoromethyl)phenyl]-4-[[5-(2-cyclopropylethynyl)-1,3-thiazol-2-yl]carbamoyl]-2-oxo-1-pyridinyl]ethanimidate	IC50	0.26 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
4-(4-acetyl-2-oxopiperazin-1-yl)-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-2-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]benzamide	IC50	0.26 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
tert-butyl 4-[4-[[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]carbamoyl]-3-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]phenyl]-3-oxopiperazine-1-carboxylate	IC50	0.26 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-[2-(4-hydroxyoxan-4-yl)ethynyl]pyridine-3-carboxamide	IC50	0.26 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-2-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-4-(1-methyl-2-oxopyrrolidin-3-yl)benzamide	IC50	0.26 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
2-(2-chloro-5-methoxy-4-pyridinyl)-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-(2-oxopyrrolidin-1-yl)benzamide	IC50	0.27 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxamide	IC50	0.27 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(3,3,4-trimethyl-2-oxopiperazin-1-yl)pyridine-3-carboxamide	IC50	0.27 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-[1-(2-methoxyethyl)pyrazol-3-yl]pyridine-3-carboxamide	IC50	0.27 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3-thiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)pyridine-3-carboxamide	IC50	0.27 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
3-[5-methoxy-2-(trifluoromethyl)-4-pyridinyl]-N-[5-(2-spiro[2.2]pentan-2-ylethynyl)-1,3,4-thiadiazol-2-yl]pyridine-4-carboxamide	IC50	0.28 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-[2-(oxan-4-yl)ethynyl]pyridine-3-carboxamide	IC50	0.28 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
5-[2-chloro-5-(trifluoromethyl)phenyl]-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-1-[2-(dimethylamino)-2-oxoethyl]-2-oxopyridine-4-carboxamide	IC50	0.29 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-2-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-4-(1-methyl-6-oxo-3-pyridinyl)benzamide	IC50	0.29 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3-thiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-[2-(oxolan-3-yl)ethynyl]pyridine-3-carboxamide	IC50	0.29 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-imidazol-1-ylpyridine-3-carboxamide	IC50	0.29 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
4-[acetyl(methyl)amino]-2-(2-chloro-5-methoxy-4-pyridinyl)-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]benzamide	IC50	0.29 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-[1-(oxan-4-yl)pyrazol-4-yl]pyridine-3-carboxamide	IC50	0.3 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(5-methyl-1,3-oxazol-2-yl)pyridine-3-carboxamide	IC50	0.3 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-3-(2,5-dichloro-4-pyridinyl)pyridine-4-carboxamide	IC50	0.31 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
2-(2-chloro-5-methoxy-4-pyridinyl)-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(4-hydroxyoxan-4-yl)ethynyl]benzamide	IC50	0.31 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
5-(2-chloro-5-methoxy-4-pyridinyl)-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-1-[2-(methylamino)-2-oxoethyl]-2-oxopyridine-4-carboxamide	IC50	0.31 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-[[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methoxy]pyridine-3-carboxamide	IC50	0.31 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3-thiazol-2-yl]-2-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-4-[2-(dimethylamino)-2-oxoethyl]benzamide	IC50	0.31 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(2-methyl-1,3-oxazol-5-yl)pyridine-3-carboxamide	IC50	0.31 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(4-methoxy-6-oxopyridazin-1-yl)pyridine-3-carboxamide	IC50	0.31 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-5-[2-methoxy-5-(trifluoromethyl)phenyl]-1-[2-(methylamino)-2-oxoethyl]-2-oxopyridine-4-carboxamide	IC50	0.32 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(2-oxopiperidin-1-yl)pyridine-3-carboxamide	IC50	0.33 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-(4-hydroxy-3,3-dimethylbut-1-ynyl)pyridine-3-carboxamide	IC50	0.33 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-[(2R)-2-(4-cyanophenyl)cyclopropyl]-1,3,4-thiadiazol-2-yl]-2-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzamide	IC50	0.34 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-2-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-4-[(3-hydroxy-3-methylcyclobutanecarbonyl)-(trideuteriomethyl)amino]benzamide	IC50	0.35 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-2-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-4-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]benzamide	IC50	0.35 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
6-chloro-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]pyridine-3-carboxamide	IC50	0.35 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
2-(2-chloro-5-methoxy-4-pyridinyl)-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-(1,3-thiazol-2-yloxy)benzamide	IC50	0.35 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
3-(2-chloro-5-methoxy-4-pyridinyl)-N-[5-[2-[4-(difluoromethoxy)phenyl]cyclopropyl]-1,3,4-thiadiazol-2-yl]pyridine-4-carboxamide	IC50	0.36 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
1-(2-amino-2-oxoethyl)-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-5-[5-(difluoromethyl)-2-methoxyphenyl]-2-oxopyridine-4-carboxamide	IC50	0.36 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
5-(2-chloro-5-methoxy-4-pyridinyl)-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-1-[2-(dimethylamino)-2-oxoethyl]-2-oxopyridine-4-carboxamide	IC50	0.36 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
3-(5-chloro-2-methoxyphenyl)-N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]pyridine-4-carboxamide	IC50	0.37 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA
N-[5-(2-cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridinyl]-6-[[(3S)-oxolan-3-yl]methoxy]pyridine-3-carboxamide	IC50	0.37 nM	US-20250026748: N-(5-SUBSTITUTED-[(1,3,4-THIADIAZOLYL) OR (THIAZOLYL)])(SUBSTITUTED)CARBOXAMIDE COMPOUNDS AND USE THEREOF FOR INHIBITING HUMAN POLYMERASE THETA

ChEMBL bioactivities

360 potent at pChembl≥5 of 367 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.17	IC50	0.068	nM	CHEMBL5204203
9.70	IC50	0.2	nM	CHEMBL5175156
9.40	IC50	0.4	nM	CHEMBL5206022
9.29	IC50	0.51	nM	CHEMBL5197367
9.26	IC50	0.55	nM	CHEMBL5187422
9.14	IC50	0.72	nM	CHEMBL5174509
9.12	IC50	0.75	nM	CHEMBL5197173
9.09	IC50	0.82	nM	CHEMBL5170373
9.04	IC50	0.91	nM	CHEMBL5194637
9.00	IC50	0.99	nM	CHEMBL5197021
8.92	IC50	1.2	nM	CHEMBL5187337
8.85	IC50	1.4	nM	CHEMBL5188048
8.80	IC50	1.6	nM	CHEMBL5181369
8.77	IC50	1.7	nM	CHEMBL5174376
8.70	IC50	2	nM	CHEMBL5429065
8.68	IC50	2.1	nM	CHEMBL5200250
8.62	IC50	2.4	nM	CHEMBL5566472
8.60	IC50	2.5	nM	CHEMBL5174283
8.54	IC50	2.9	nM	CHEMBL5195161
8.41	IC50	3.9	nM	CHEMBL5194194
8.39	IC50	4.1	nM	CHEMBL5208956
8.38	IC50	4.2	nM	CHEMBL5206029
8.32	Kd	4.8	nM	CHEMBL5206992
8.31	IC50	4.9	nM	CHEMBL5202450
8.30	IC50	5	nM	CHEMBL5418074
8.30	IC50	5.012	nM	CHEMBL6172090
8.27	IC50	5.4	nM	CHEMBL5205456
8.24	IC50	5.8	nM	CHEMBL5187422
8.24	IC50	5.8	nM	CHEMBL5591828
8.23	IC50	5.9	nM	CHEMBL5190089
8.19	Kd	6.4	nM	CHEMBL5206992
8.17	IC50	6.8	nM	CHEMBL5175531
8.15	IC50	7	nM	CHEMBL5176919
8.15	IC50	7	nM	CHEMBL5411191
8.13	IC50	7.49	nM	CHEMBL5195920
8.12	IC50	7.6	nM	CHEMBL5191330
8.10	IC50	7.9	nM	CHEMBL5206992
8.10	IC50	7.9	nM	CHEMBL5573055
8.10	IC50	7.943	nM	CHEMBL6134385
8.09	Kd	8.2	nM	CHEMBL5206829
8.07	IC50	8.479	nM	CHEMBL5195920
8.06	IC50	8.714	nM	CHEMBL5195920
8.06	IC50	8.8	nM	CHEMBL5180095
8.05	IC50	9	nM	CHEMBL5200171
8.03	IC50	9.4	nM	CHEMBL5200410
8.00	IC50	10	nM	CHEMBL5195920
8.00	IC50	10	nM	CHEMBL6163075
7.96	Kd	11	nM	CHEMBL5206829
7.95	IC50	11.13	nM	CHEMBL5195920
7.90	IC50	12.59	nM	CHEMBL6172559

PubChem BioAssay actives

159 with measured affinity, of 220 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-[4-(N-[2-[2,4-bis(trifluoromethyl)phenyl]acetyl]anilino)but-2-ynyl]-5-methyl-1,3,4-oxadiazole-2-carboxamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0001	uM
N-[4-(N-[2-[2,4-bis(trifluoromethyl)phenyl]acetyl]anilino)but-2-ynyl]pyridine-3-carboxamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0002	uM
N-[4-(N-[2-[2,4-bis(trifluoromethyl)phenyl]acetyl]anilino)but-2-ynyl]pyridine-2-carboxamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0004	uM
2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(6-oxo-1H-pyridin-2-yl)prop-2-ynyl]-N-phenylacetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0005	uM
N-[3-(6-aminopyridazin-3-yl)prop-2-ynyl]-2-[3,5-bis(trifluoromethyl)-2-pyridinyl]-N-(4-fluorophenyl)acetamide	1856655: Inhibition of N-terminal His8-tagged/C-terminal FLAG-tagged full length human DNA polymerase theta ( 1 to 2590 residues) polymerase activity expressed in HEK2936E cells	ic50	0.0006	uM
2-[3,5-bis(trifluoromethyl)-2-pyridinyl]-N-(4-fluorophenyl)-N-[3-(5-pyrrolidin-3-yl-2-pyridinyl)prop-2-ynyl]acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0007	uM
N-(4-acetamidobut-2-ynyl)-2-[2,4-bis(trifluoromethyl)phenyl]-N-phenylacetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0008	uM
N-[3-[1-(azetidin-3-yl)pyrazol-4-yl]prop-2-ynyl]-2-[3,5-bis(trifluoromethyl)-2-pyridinyl]-N-(4-fluorophenyl)acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0008	uM
2-[3,5-bis(trifluoromethyl)-2-pyridinyl]-N-(4-fluorophenyl)-N-[3-[1-(methylsulfonylmethyl)pyrazol-4-yl]prop-2-ynyl]acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0009	uM
2-[4-[3-(N-[2-[3,5-bis(trifluoromethyl)-2-pyridinyl]acetyl]-4-fluoroanilino)prop-1-ynyl]pyrazol-1-yl]propanamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0010	uM
2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-methylimidazol-4-yl)prop-2-ynyl]-N-phenylacetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0012	uM
2-[2,4-bis(trifluoromethyl)phenyl]-N-phenyl-N-(3-pyridazin-3-ylprop-2-ynyl)acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0014	uM
N-[3-(2-aminopyrimidin-5-yl)prop-2-ynyl]-2-[3,5-bis(trifluoromethyl)-2-pyridinyl]-N-(4-fluorophenyl)acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0016	uM
N-[3-(3-amino-1-methylpyrazol-5-yl)prop-2-ynyl]-2-[3,5-bis(trifluoromethyl)-2-pyridinyl]-N-(4-fluorophenyl)acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0017	uM
1-[6-[3-methyl-4-[(3-methyloxolan-3-yl)methoxy]phenyl]pyrazin-2-yl]-3-(6-methyl-3-pyridinyl)urea	1988497: Inhibition of N-terminal/C-termianl Flag-tagged POLQ (unknown origin) (2 to 2590 residues) expressed in baculovirus incubated for 30 mins by fluorescence based analysis	ic50	0.0020	uM
2-[3,5-bis(trifluoromethyl)-2-pyridinyl]-N-(4-fluorophenyl)-N-[3-(2-methoxypyrimidin-5-yl)prop-2-ynyl]acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0021	uM
N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-3-(2-methoxyphenyl)pyridine-4-carboxamide	2080474: Inhibition of human DNA polymerase theta (67 to 970 residues) ATPase activity expressed in Sf9 insect cells incubated for 40 mins by ADP-glo assay	ic50	0.0024	uM
2-[2,4-bis(trifluoromethyl)phenyl]-N-phenyl-N-(3-pyridin-3-ylprop-2-ynyl)acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0025	uM
2-[2,4-bis(trifluoromethyl)phenyl]-N-phenyl-N-(3-pyridin-2-ylprop-2-ynyl)acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0029	uM
2-[2,4-bis(trifluoromethyl)phenyl]-N-phenyl-N-(3-pyrimidin-2-ylprop-2-ynyl)acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0039	uM
(4S)-N-(2,4-difluoro-3-methylphenyl)-N-methyl-3-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-2-oxo-1,3-oxazolidine-4-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0041	uM
N-[3-(5-aminopyrazin-2-yl)prop-2-ynyl]-2-[3,5-bis(trifluoromethyl)-2-pyridinyl]-N-(4-fluorophenyl)acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0042	uM
(2S,3R)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-3-hydroxy-N-methyl-N-(3-methylphenyl)pyrrolidine-2-carboxamide	1857358: Displacement of tracer from recombinant Tb-labeled DNA polymerase theta (unknown origin) using DNA as substrate preincubated for 30 mins followed by compound addition for 2 hrs by HTRF assay	kd	0.0048	uM
2-[3,5-bis(trifluoromethyl)-2-pyridinyl]-N-(4-fluorophenyl)-N-[3-(6-methoxypyridazin-3-yl)prop-2-ynyl]acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0049	uM
(4R)-4-[4-chloro-1-(3-chloro-4-fluorophenyl)imidazol-2-yl]-3-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-1,3-oxazolidin-2-one	1988499: Inhibition of POLQ PD (unknown origin) (1819 to 2590 residues) incubated for 15 mins by fluorescence based analysis	ic50	0.0050	uM
4-[3-[4-[9-benzyl-6-(1-methylcyclopropyl)oxypurin-8-yl]-3-chlorophenoxy]propyl]piperazin-2-one	2241578: Inhibition of human DNA polymerase theta using dTTP as substrate incubated for 1 hr PPiLight inorganic pyrophosphate assay	ic50	0.0050	uM
(4S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-2-oxo-1,3-oxazolidine-4-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0054	uM
N-[3-(6-aminopyridazin-3-yl)prop-2-ynyl]-N-(4-fluorophenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]acetamide	2107386: Inhibition of DNA polymerase theta (unknown origin) using 5-TAMRA-CCTTCCTCCCGTGTCTTGTACCTTCCCGTCAGGAGGAAGG-BHQ-3’ as substrate incubated for 60 mins by fluorescence analysis	ic50	0.0058	uM
(2S,3R)-N-(3-chloro-4-fluorophenyl)-3-hydroxy-N-methyl-1-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-5-oxopyrrolidine-2-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0059	uM
(2S)-N-methyl-N-(3-methylphenyl)-1-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-5-oxopyrrolidine-2-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0068	uM
1-[2-[3-methyl-4-[[(3R)-3-methyloxolan-3-yl]methoxy]phenyl]-1,3-thiazol-4-yl]-3-[(3S)-piperidin-3-yl]urea	1988497: Inhibition of N-terminal/C-termianl Flag-tagged POLQ (unknown origin) (2 to 2590 residues) expressed in baculovirus incubated for 30 mins by fluorescence based analysis	ic50	0.0070	uM
(4S)-N-methyl-N-(3-methylphenyl)-3-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-2-oxo-1,3-oxazolidine-4-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0070	uM
N-methyl-N-phenyl-2-[3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethanethioamide	1856691: Inhibition of human DNA polymerase theta using DNA 16/19 as substrate at 1 nM of enzyme concentration	ic50	0.0075	uM
(2S,3S,4S)-N-(3-chloro-4-fluorophenyl)-3,4-dihydroxy-N-methyl-1-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-5-oxopyrrolidine-2-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0076	uM
(2S,3R)-N-(3-chloro-4-fluorophenyl)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-3-hydroxy-N-methylpyrrolidine-2-carboxamide	2107386: Inhibition of DNA polymerase theta (unknown origin) using 5-TAMRA-CCTTCCTCCCGTGTCTTGTACCTTCCCGTCAGGAGGAAGG-BHQ-3’ as substrate incubated for 60 mins by fluorescence analysis	ic50	0.0079	uM
9-benzyl-8-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-propan-2-yloxypurine	2241578: Inhibition of human DNA polymerase theta using dTTP as substrate incubated for 1 hr PPiLight inorganic pyrophosphate assay	ic50	0.0079	uM
(2S,4S)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-4-hydroxy-N-methyl-N-(3-methylphenyl)pyrrolidine-2-carboxamide	1857358: Displacement of tracer from recombinant Tb-labeled DNA polymerase theta (unknown origin) using DNA as substrate preincubated for 30 mins followed by compound addition for 2 hrs by HTRF assay	kd	0.0082	uM
(2S)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-N-(3-methylphenyl)-N-propan-2-ylpyrrolidine-2-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0088	uM
2-[3,5-bis(trifluoromethyl)-2-pyridinyl]-N-(4-fluorophenyl)-N-[3-(1-methylimidazol-4-yl)prop-2-ynyl]acetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0090	uM
(4S)-N-(4-fluoro-3-methylphenyl)-N-methyl-3-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-2-oxo-1,3-oxazolidine-4-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0094	uM
8-[6-(azetidin-3-yloxy)-4-methyl-3-pyridinyl]-9-benzyl-6-(1-methylcyclopropyl)oxypurine	2241578: Inhibition of human DNA polymerase theta using dTTP as substrate incubated for 1 hr PPiLight inorganic pyrophosphate assay	ic50	0.0100	uM
8-[2-chloro-4-(2-piperazin-1-ylethoxy)phenyl]-9-[(6-chloro-2-pyridinyl)methyl]-6-(1-methylcyclopropyl)oxypurine	2241578: Inhibition of human DNA polymerase theta using dTTP as substrate incubated for 1 hr PPiLight inorganic pyrophosphate assay	ic50	0.0126	uM
4-[[8-[2-chloro-4-(2-piperazin-1-ylethoxy)phenyl]-6-(1-methylcyclopropyl)oxypurin-9-yl]methyl]-2-methyl-1,3-thiazole	2241578: Inhibition of human DNA polymerase theta using dTTP as substrate incubated for 1 hr PPiLight inorganic pyrophosphate assay	ic50	0.0126	uM
8-[2-chloro-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(1-methylcyclopropyl)oxy-9-(pyrimidin-2-ylmethyl)purine	2241578: Inhibition of human DNA polymerase theta using dTTP as substrate incubated for 1 hr PPiLight inorganic pyrophosphate assay	ic50	0.0126	uM
2-[2,4-bis(trifluoromethyl)phenyl]-N-phenyl-N-prop-2-ynylacetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0140	uM
2-[2,4-bis(trifluoromethyl)phenyl]-N-methyl-N-phenylacetamide	1856651: Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence intensity analysis	ic50	0.0140	uM
(4S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-2-oxo-1,3-oxazolidine-4-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0150	uM
(4S)-N-(3-chlorophenyl)-N-methyl-3-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-2-oxo-1,3-oxazolidine-4-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0150	uM
(4S)-N-(3-chloro-2-fluorophenyl)-N-methyl-3-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-2-oxo-1,3-oxazolidine-4-carboxamide	1857356: Inhibition of recombinant human full length DNA polymerase theta using DNA substrate measured after 1 hrs in presence of dNTPs by plate reader assay	ic50	0.0150	uM
(2S,4S)-N-(3-chloro-4-fluorophenyl)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-4-hydroxy-N-methylpyrrolidine-2-carboxamide	1988499: Inhibition of POLQ PD (unknown origin) (1819 to 2590 residues) incubated for 15 mins by fluorescence based analysis	ic50	0.0160	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression	3
Valproic Acid	affects cotreatment, increases expression	3
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
afuresertib	decreases expression	1
lasiocarpine	increases expression	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
N(4)-hydroxycytidine	increases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cypermethrin	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
CPG-oligonucleotide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
trans-10,cis-12-conjugated linoleic acid	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	increases expression	1
incobotulinumtoxinA	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Dasatinib	decreases expression	1
Sunitinib	decreases expression	1
Troglitazone	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1

ChEMBL screening assays

46 unique, capped per target: 46 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5111529	Binding	Inhibition of human DNA polymerase theta pol domain (1819 to 2590 residues) expressed in Escherichia coli BL21 (DE3) cells preincubated for 15 mins followed by DNA and dNTP addition and measured after 120 mins by Picogreen dye fluorescence	Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ. — *J Med Chem*

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8MR	Abcam HCT 116 POLQ KO	Cancer cell line	Male
CVCL_B9AF	Abcam MCF-7 POLQ KO	Cancer cell line	Female
CVCL_B9Q0	Abcam A-549 POLQ KO	Cancer cell line	Male
CVCL_D9NY	Ubigene HEK293 POLQ KO	Transformed cell line	Female
CVCL_F4IP	HyCyte RKO KO-hPOLQ	Cancer cell line	Sex unspecified
CVCL_TF12	HAP1 POLQ (-) 1	Cancer cell line	Male
CVCL_TF13	HAP1 POLQ (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 78 trials:

NCT	Phase	Status	Title
NCT02562170	Phase 4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00104676	Phase 3	COMPLETED	Combination Chemotherapy in Treating Patients With Stage II or Stage III Germ Cell Tumors
NCT02375204	Phase 3	ACTIVE_NOT_RECRUITING	Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors
NCT00673335	Phase 3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	Phase 3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	Phase 3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00002931	Phase 2	COMPLETED	Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Relapsed Germ Cell Cancer
NCT00301782	Phase 2	COMPLETED	Combination Chemotherapy in Treating Male Patients With Germ Cell Tumors
NCT00432094	Phase 2	COMPLETED	Autologous Peripheral Blood Stem Cell Transplant for Germ Cell Tumors
NCT00453232	Phase 2	COMPLETED	Combination Chemotherapy and Pegfilgrastim in Treating Men With Metastatic Germ Cell Tumors
NCT00453310	Phase 2	COMPLETED	Sunitinib in Treating Patients With Metastatic Germ Cell Tumors That Have Relapsed or Not Responded to Treatment
NCT00470366	Phase 2	COMPLETED	Combination Chemotherapy and Pegfilgrastim in Treating Patients With Previously Untreated Germ Cell Tumors
NCT02300987	Phase 2	COMPLETED	A Randomized, Blinded, Placebo-controlled, Phase II Trial of LEE011 in Patients With Relapsed, Refractory, Incurable Teratoma With Recent Progression
NCT00253539	Phase 2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	Phase 2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	Phase 2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	Phase 2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	Phase 2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	Phase 1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	Phase 1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT00040222	Not specified	COMPLETED	Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer
NCT02557776	Not specified	COMPLETED	Written Genetic Counseling and Mutation Analysis of BRCA1 and BRCA2 to Patients With Breast Cancer
NCT03495544	Not specified	UNKNOWN	Study Estimating Association Between Germline Mutations and PD-L1 Expression in Breast Cancer
NCT03959267	Not specified	COMPLETED	Testing a Culturally Adapted Telephone Genetic Counseling Intervention
NCT04058418	Not specified	COMPLETED	Specialist Recommendation on FBC (Familial Breast Cancer) Chemoprevention Prescribing
NCT04125914	Not specified	ACTIVE_NOT_RECRUITING	Weight Management and Health Behavior Intervention in Lowering Cancer Risk for BRCA Positive and Lynch Syndrome Families
NCT04169542	Not specified	RECRUITING	Impact of COVID-19 Pandemic on Out-of-Pocket Costs, Lost Wages, and Unemployment in Patients With Breast Cancer Undergoing Breast Surgery
NCT04197856	Not specified	UNKNOWN	Direct Information to At-risk Relatives
NCT07292246	Not specified	RECRUITING	A Prospective CohorT Study of HandX - Assisted ENdoscopic MAstectomy: Feasibility and Safety (ATHENA I Study)
NCT07307664	Not specified	RECRUITING	Increasing Germline Genetic Testing for Patients With Cancer
NCT00003643	Phase 2/3	UNKNOWN	Combination Chemotherapy in Treating Men With Germ Cell Cancer
NCT00423852	Phase 1/2	COMPLETED	Paclitaxel, Ifosfamide, and Carboplatin Followed By Autologous Stem Cell Transplant in Treating Patients With Germ Cell Tumors That Did Not Respond to Cisplatin
NCT00687778	Not specified	UNKNOWN	11C-Acetate PET/CT Non-FDG-Avid Tumors
NCT00836121	Not specified	COMPLETED	Anterior Mediastinum Teratoma: A Case Report
NCT05179850	Not specified	UNKNOWN	Computer Aided Diagnostic Tool on Computed Tomography Images for Diagnosis of Retroperitoneal Tumor in Children
NCT05187923	Not specified	UNKNOWN	Computer Aided Tool for Diagnosis of Neck Masses in Children
NCT05564026	Not specified	RECRUITING	Molecular Epidemiology of Pediatric Germ Cell Tumors
NCT06421805	Not specified	RECRUITING	Establishing Prospective Mediastinal Tumor Database of PUMCH
NCT07199699	Not specified	NOT_YET_RECRUITING	Subxiphoid VATS for Giant Mediastinal Teratoma
NCT03832985	Early Phase 1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for POLQ across ~30M SureChEMBL compounds — explore on Sugi Predict.