ATR

Summary

ATR (ATR checkpoint kinase, HGNC:882) is a protein-coding gene on chromosome 3q23, encoding Serine/threonine-protein kinase ATR (Q13535). Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor.

The protein encoded by this gene is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling upon DNA stress. The encoded protein can phosphorylate and activate several proteins involved in the inhibition of DNA replication and mitosis, and can promote DNA repair, recombination, and apoptosis. This protein is also important for fragile site stability and centrosome duplication. Defects in this gene are a cause of Seckel syndrome 1.

Source: NCBI Gene 545 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Seckel syndrome 1 (Definitive, GenCC) — +4 more curated relationships
• Clinical variants (ClinVar): 4,233 total — 93 pathogenic, 47 likely-pathogenic (top 1% of genes corpus-wide)
• Regional missense constraint (gnomAD): 2 of 9 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 26 tissues, sQTL in 4 (q < 0.05)
• Drug target: yes — 4 curated mechanism-of-action drugs; 8 molecules with ChEMBL bioactivity
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.52 (moderately constrained)
• MANE Select transcript: NM_001184
• Interaction hub: 2,422 STRING partners (top 5% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:882
Approved symbol	ATR
Name	ATR checkpoint kinase
Location	3q23
Locus type	gene with protein product
Status	Approved
Aliases	FRP1, SCKL, SCKL1, MEC1
Ensembl gene	ENSG00000175054
Ensembl biotype	protein_coding
OMIM	601215
Entrez	545

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 15 retained_intron, 9 protein_coding, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000350721

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1, TSL 3: 3, TSL 4: 2, TSL 5: 1

ENST00000350721, ENST00000507148, ENST00000507620, ENST00000511016, ENST00000513291, ENST00000514393, ENST00000515149, ENST00000515810, ENST00000515863, ENST00000653868, ENST00000653893, ENST00000654170, ENST00000656114, ENST00000656582, ENST00000656590, ENST00000657914, ENST00000658083, ENST00000659195, ENST00000661310, ENST00000665483, ENST00000666447, ENST00000666943, ENST00000892891, ENST00000936442, ENST00000936443, ENST00001064457, ENST00001110148, ENST00001115651, ENST00001124137, ENST00001144791

RefSeq mRNA: 2 — MANE Select: NM_001184 NM_001184, NM_001354579

CCDS: CCDS3124, CCDS93402

Canonical transcript exons

ENST00000350721 — 47 exons

Exon	Start	End
ENSE00001205280	142496361	142496520
ENSE00001205292	142458958	142459111
ENSE00001205296	142459227	142459383
ENSE00001205300	142461940	142462090
ENSE00001205303	142465097	142465240
ENSE00001205308	142466324	142466533
ENSE00001205312	142467934	142468068
ENSE00001205316	142469337	142469569
ENSE00001205322	142470086	142470183
ENSE00001229183	142457604	142457755
ENSE00001229256	142493132	142493311
ENSE00001229291	142499627	142499718
ENSE00001229298	142503362	142503453
ENSE00001229310	142505139	142505303
ENSE00001229320	142507931	142508109
ENSE00001229328	142512260	142512470
ENSE00001229336	142513501	142513638
ENSE00001229346	142515395	142515515
ENSE00001229354	142519669	142519784
ENSE00001229360	142522728	142522841
ENSE00001229365	142523993	142524199
ENSE00001229371	142535080	142535205
ENSE00001229377	142536108	142536201
ENSE00001229380	142538482	142538625
ENSE00001229387	142540904	142541034
ENSE00001229397	142542665	142542757
ENSE00001229405	142547725	142547910
ENSE00001229413	142549479	142549673
ENSE00001229418	142550132	142550302
ENSE00001229428	142553227	142553398
ENSE00001229432	142553640	142553740
ENSE00001229438	142553825	142554015
ENSE00001229447	142555877	142556139
ENSE00001229459	142558624	142558776
ENSE00001229465	142559251	142559441
ENSE00001229471	142560263	142560454
ENSE00001229477	142562232	142563109
ENSE00001229482	142566121	142566261
ENSE00001229531	142568063	142568154
ENSE00001369208	142578646	142578733
ENSE00001416709	142485140	142485282
ENSE00003496871	142453128	142453233
ENSE00003515923	142449235	142449602
ENSE00003591356	142498597	142498774
ENSE00003609500	142561243	142561421
ENSE00003609638	142497013	142497192
ENSE00003785032	142556383	142556575

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 95.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.4913 / max 108.7795, expressed in 1780 samples.

Highest expression (Bgee): Brodmann (1909) area 23, epithelium of nasopharynx, adrenal tissue, endothelial cell, caput epididymis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ATR is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 26 tissues and its splicing (sQTL) in 4 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 30 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	5.3e-10	-0.18	3:142455574:C:T
Muscle Skeletal	eqtl	1.1e-07	+0.14	3:142404445:GA:G
Thyroid	eqtl	1.8e-06	-0.18	3:142618962:G:A
Brain Cortex	eqtl	6.6e-05	-0.21	3:142474703:T:A
Skin Not Sun Exposed Suprapubic	eqtl	1.1e-04	-0.16	3:142601690:A:T
Pituitary	eqtl	1.3e-04	-0.22	3:142589135:G:A
Artery Aorta	eqtl	1.8e-04	+0.92	3:142693809:T:TTACTATGA
Brain Cerebellum	eqtl	3.8e-04	-0.23	3:142639688:A:G
Brain Anterior cingulate cortex BA24	eqtl	5.6e-04	-0.20	3:142631202:T:C
Brain Caudate basal ganglia	eqtl	7.8e-04	-0.18	3:142491959:G:A
Adipose Subcutaneous	eqtl	1.6e-03	-0.12	3:142621965:A:G
Lung	eqtl	1.7e-03	-0.13	3:142243095:T:C
Spleen	eqtl	2.1e-03	-0.22	3:142334975:ACAG:A
Prostate	eqtl	3.3e-03	-0.24	3:142297932:A:G
Brain Putamen basal ganglia	eqtl	3.4e-03	-0.19	3:142691935:A:C
Skin Sun Exposed Lower leg	sqtl	5.0e-03	-0.33	3:142819807:G:A
Brain Nucleus accumbens basal ganglia	eqtl	5.4e-03	-0.19	3:142475194:C:T
Brain Frontal Cortex BA9	eqtl	6.6e-03	+0.82	3:142181412:T:C
Colon Transverse	eqtl	6.9e-03	+0.67	3:142693809:T:TTACTATGA
Testis	eqtl	1.2e-02	-0.11	3:142297932:A:G

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
44854	13.4833	1780
44853	0.0081	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	95.65	gold quality
epithelium of nasopharynx	UBERON:0001951	94.49	gold quality
adrenal tissue	UBERON:0018303	93.26	gold quality
endothelial cell	CL:0000115	93.14	gold quality
caput epididymis	UBERON:0004358	92.29	gold quality
tibia	UBERON:0000979	92.25	gold quality
choroid plexus epithelium	UBERON:0003911	92.21	gold quality
corpus epididymis	UBERON:0004359	91.88	gold quality
germinal epithelium of ovary	UBERON:0001304	91.54	gold quality
middle temporal gyrus	UBERON:0002771	91.52	gold quality
bronchial epithelial cell	CL:0002328	91.29	gold quality
skin of hip	UBERON:0001554	91.10	gold quality
visceral pleura	UBERON:0002401	90.97	gold quality
gingival epithelium	UBERON:0001949	90.87	gold quality
cauda epididymis	UBERON:0004360	90.78	gold quality
parietal pleura	UBERON:0002400	90.72	gold quality
right adrenal gland cortex	UBERON:0035827	90.59	gold quality
adrenal cortex	UBERON:0001235	90.48	gold quality
left adrenal gland cortex	UBERON:0035825	90.33	gold quality
pleura	UBERON:0000977	90.27	gold quality
right adrenal gland	UBERON:0001233	90.11	gold quality
adrenal gland	UBERON:0002369	90.06	gold quality
left adrenal gland	UBERON:0001234	89.95	gold quality
primary visual cortex	UBERON:0002436	89.62	gold quality
granulocyte	CL:0000094	89.25	gold quality
tonsil	UBERON:0002372	89.03	gold quality
cervix squamous epithelium	UBERON:0006922	88.86	gold quality
sperm	CL:0000019	88.82	gold quality
epithelium of bronchus	UBERON:0002031	88.80	gold quality
pigmented layer of retina	UBERON:0001782	88.78	gold quality
gingiva	UBERON:0001828	88.78	gold quality
endometrium	UBERON:0001295	88.73	gold quality
bronchus	UBERON:0002185	88.47	gold quality
endometrium epithelium	UBERON:0004811	88.08	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.61	gold quality
oral cavity	UBERON:0000167	87.54	gold quality
calcaneal tendon	UBERON:0003701	87.37	gold quality
colonic epithelium	UBERON:0000397	87.17	gold quality
CA1 field of hippocampus	UBERON:0003881	87.06	gold quality
hair follicle	UBERON:0002073	87.05	gold quality
squamous epithelium	UBERON:0006914	86.97	gold quality
seminal vesicle	UBERON:0000998	86.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.64	gold quality
colonic mucosa	UBERON:0000317	86.49	gold quality
male germ cell	CL:0000015	86.42	gold quality
epithelium of mammary gland	UBERON:0003244	86.42	gold quality
spleen	UBERON:0002106	86.40	gold quality
mammary gland	UBERON:0001911	86.37	gold quality
oocyte	CL:0000023	86.30	gold quality
thoracic mammary gland	UBERON:0005200	86.30	gold quality
mammary duct	UBERON:0001765	86.16	gold quality
bone marrow cell	CL:0002092	86.04	gold quality
renal glomerulus	UBERON:0000074	86.04	gold quality
palpebral conjunctiva	UBERON:0001812	85.85	gold quality
oviduct epithelium	UBERON:0004804	85.72	gold quality
adenohypophysis	UBERON:0002196	85.68	gold quality
body of pancreas	UBERON:0001150	85.67	gold quality
right uterine tube	UBERON:0001302	85.62	gold quality
superficial temporal artery	UBERON:0001614	85.51	gold quality
esophagus squamous epithelium	UBERON:0006920	85.48	gold quality
upper leg skin	UBERON:0004262	85.47	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.35	gold quality
metanephric glomerulus	UBERON:0004736	85.34	gold quality
uterus	UBERON:0000995	85.30	gold quality
occipital lobe	UBERON:0002021	85.23	gold quality
Brodmann (1909) area 10	UBERON:0013541	85.11	gold quality
right lobe of liver	UBERON:0001114	85.07	gold quality
pituitary gland	UBERON:0000007	85.03	gold quality
secondary oocyte	CL:0000655	84.95	gold quality
nephron tubule	UBERON:0001231	84.85	gold quality
adipose tissue	UBERON:0001013	84.66	gold quality
blood vessel layer	UBERON:0004797	84.64	gold quality
connective tissue	UBERON:0002384	84.60	gold quality
cortex of kidney	UBERON:0001225	84.51	gold quality
parotid gland	UBERON:0001831	84.41	gold quality
thyroid gland	UBERON:0002046	84.33	gold quality
left lobe of thyroid gland	UBERON:0001120	84.25	gold quality
nasal cavity mucosa	UBERON:0001826	84.18	gold quality
sural nerve	UBERON:0015488	84.17	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.02	gold quality
tendon	UBERON:0000043	84.00	gold quality
metanephros	UBERON:0000081	83.99	gold quality
cerebellar hemisphere	UBERON:0002245	83.99	gold quality
cerebellar cortex	UBERON:0002129	83.98	gold quality
lymph node	UBERON:0000029	83.84	gold quality
leukocyte	CL:0000738	83.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.72	gold quality
mononuclear cell	CL:0000842	83.62	gold quality
right lobe of thyroid gland	UBERON:0001119	83.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.59	gold quality
pancreas	UBERON:0001264	83.59	gold quality
ectocervix	UBERON:0012249	83.55	gold quality
monocyte	CL:0000576	83.54	gold quality
trabecular bone tissue	UBERON:0002483	83.52	gold quality
mucosa of transverse colon	UBERON:0004991	83.51	gold quality
bone marrow	UBERON:0002371	83.49	gold quality
fallopian tube	UBERON:0003889	83.44	gold quality
ventricular zone	UBERON:0003053	83.40	gold quality
female reproductive system	UBERON:0000474	83.38	gold quality
Ammon’s horn	UBERON:0001954	83.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 152 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Choroid plexus	tissue	151.2
Ovary	tissue	128.0
Gallbladder	tissue	107.2
Endometrium 1	tissue	76.4
Placenta	tissue	74.0
Cervix	tissue	73.1
Hippocampus	tissue	61.8
Adrenal gland	tissue	59.6
Smooth muscle	tissue	58.0
Spinal cord	tissue	54.4
Seminal vesicle	tissue	52.1
Urinary bladder	tissue	48.9
Superior colliculi	tissue	47.5
Prostate	tissue	45.0
Locus coeruleus	tissue	44.2
Vagina	tissue	42.5
Lung	tissue	41.6
Medulla oblongata	tissue	40.7
Thyroid gland	tissue	40.6
Substantia nigra	tissue	40.2
Periaqueductal gray	tissue	38.9
Skin 1	tissue	37.1
Midbrain	tissue	37.1
Thalamus	tissue	33.9
Fallopian tube	tissue	33.8
Parathyroid gland	tissue	33.3
Nucleus accumbens	tissue	32.3
Esophagus	tissue	31.8
Heart muscle	tissue	30.6
Pons	tissue	29.9
Hypothalamus	tissue	29.4
Olfactory bulb	tissue	29.0
Adipose tissue	tissue	27.5
Hippocampal formation	tissue	27.3
Spleen	tissue	26.6
Basal ganglia	tissue	24.7
Entorhinal cortex	tissue	24.7
Breast	tissue	24.3
Cerebral cortex	tissue	24.1
Temporal cortex	tissue	24.1
Epididymis	tissue	23.8
Postcentral gyrus	tissue	23.5
Cerebellum	tissue	23.3
Putamen	tissue	23.1
Corpus callosum	tissue	23.1
Amygdala	tissue	23.0
Motor cortex	tissue	22.8
Tongue	tissue	22.5
Septum	tissue	22.4
Occipital cortex	tissue	21.8
Insular cortex	tissue	21.6
Prefrontal cortex	tissue	21.2
Somatosensory cortex	tissue	21.1
Ventral forebrain	tissue	20.8
Cerebellum	tissue	20.2
Rectum	tissue	20.1
Retrosplenial cortex	tissue	19.7
Retrosplenial and cingulate cortex	tissue	19.1
Appendix	tissue	19.1
Colon	tissue	18.8

Brain sub-regions (HPA Brain Atlas): detected in 381; highest nTPM — Blood vessel (205.1), Supraoptic nucleus (152.4), Periaquaductal grey, lateral (109.7), Periaquaductal grey, dorsal (100.5), Medial olivary nucleus (98.5).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

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

18 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-3613-5P	98.40	68.91	604
HSA-MIR-628-5P	98.36	67.74	844
HSA-MIR-383-5P	96.86	67.55	820

Functional genomics

gnomAD constraint: pLI 1.17e-07, LOEUF 0.518, missense Z 7.15 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000350721 splits into 9 regions with different missense tolerance; 2 are missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:142,449,432–142,496,501	462 / 887.6	0.52	no
3:142,496,502–142,497,059	30 / 26.7	1.12	no
3:142,497,060–142,505,166	117 / 198.3	0.59	no
3:142,505,167–142,505,233	2 / 25.0	0.08	yes (p 4.3e-06)
3:142,505,234–142,508,058	45 / 80.4	0.56	no
3:142,508,059–142,519,773	202 / 252.9	0.80	no
3:142,519,774–142,522,772	3 / 22.1	0.14	yes (p 4.7e-05)
3:142,522,773–142,555,963	530 / 766.8	0.69	no
3:142,555,964–142,578,704	744 / 873.2	0.85	no

Literature-anchored findings (GeneRIF, showing 40)

• binds novel protein called ATRIP (ATR-interacting protein); ATRIP and ATR are mutually dependent partners in cell cycle checkpoint signaling pathways (PMID:11721054)
• ATR kinase plays an important role during tumor development in responding to hypoxia-induced replication arrest, and hypoxic conditions could select for the loss of key components of ATR-dependent checkpoint controls (PMID:11865061)
• lack of role in cellular response to DNA strand-scission enediyne C-1027 (PMID:11927575)
• ATR may function as an initial sensor in the DNA damage checkpoint response to UV. (PMID:12011431)
• ATR has a role in regulating cyclin B1 phosphorylation by inhibiting Plk1 kinase activity (PMID:12147700)
• Data suggest that the UVC-induced S checkpoint response of inhibition of replicon initiation is mediated by ATR signaling through Chk-1 and is independent of ATM, Nbs1, and Mre11. (PMID:12446774)
• ATR kinase has a critical role in the response of hypoxia and reperfusion in solid tumors. (PMID:12519769)
• ATR has a role in regulating chromosomal fragile sites and DNA replication (PMID:12526805)
• WRN and ATR colocalize after replication fork arrest, suggesting that WRN and the ATR kinase collaborate to prevent genome instability during the S phase. (PMID:12629512)
• activity of the ATR kinase is required for successful completion of the viral DNA integration process and/or survival of transduced cells (PMID:12679521)
• ATR has a role in the DNA damage-signaling pathway by a viral gene product (PMID:12738771)
• BRCA1 facilitates the ability of ATM and ATR to phosphorylate downstream substrates that directly influence cell cycle checkpoint arrest and apoptosis (PMID:12773400)
• the G2 checkpoint in irradiated human cells derives from an overactivation of the ATR/CHK1 pathway. (PMID:12791699)
• data suggest that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling (PMID:12791985)
• Polyglutamine-expanded proteins strongly activated ATR. (PMID:12915485)
• hyperoxia activates the ATR-Chk1 pathway and phosphorylates p53 at multiple sites in an ATM-independent manner, which is different from other forms of oxidative stress such as H2O2 or UV light. (PMID:12959929)
• A model in which MSH2 and ATR function upstream to regulate two branches of the response pathway to DNA damage caused by MNNG. (PMID:14657349)
• there are at least two in vitro ATR-ATRIP DNA binding complexes, one which binds DNA with high affinity in an RPA-dependent manner and a second, which binds DNA with lower affinity in an RPA-independent manner (PMID:14724280)
• ATR activation is facilitated by phosphorylated H2AX stabilizing ATR at the sites of arrested replication forks (PMID:14742437)
• ATR-p53 pathway is suppressed in noncycling lymphocytes via ATR downregulation. (PMID:14755251)
• The transient slow-down of DNA synthesis was abolished in cells lacking ATR, whereas CHK1-siRNA-treated cells, NBS1 or Fanconi anemia cells showed partial S-phase arrest. (PMID:14988723)
• low-dose UV radiation activates an S-phase checkpoint requiring ATR-mediated signal transduction pathway (PMID:15235112)
• hSMG-1 teams with ATM and ATR to insure the overall quality of the transcriptome in human cells [review] (PMID:15279777)
• ATR serves as a haploinsufficient tumor suppressor in mismatch repair-deficient cells (PMID:15282542)
• ATR checkpoint kinase and RPA1 are required for efficient FANCD2 monoubiquitination (PMID:15314022)
• ATR and Chk1 play critical roles in the cellular response to hypoxia/reoxygenation in cancer cell lines, and inhibitors of ATR and Chk1 represent new hypoxic cell cytotoxins. (PMID:15374968)
• Data show that Artemis interacts with cell cycle checkpoint proteins and is a phosphorylation target of the checkpoint kinases ATM or ATR after exposure of cells to IR or UV irradiation, respectively. (PMID:15456891)
• Effects of ATR on cell radiosensitivity are independent of NHEJ but are linked to HRR that may be affected by the deficient S and G(2) checkpoints. (PMID:15466211)
• N-terminal domain of the ATRIP protein contributes to the cell cycle checkpoint by regulating the intranuclear localization of ATR (PMID:15527801)
• data reveal activated ATM and ATR exhibit selective substrate specificity in response to DNA damage (PMID:15533933)
• Thus, optimal repair of damaged replication fork lesions likely requires both ATR and ATM. BLM recruits 53BP1 to these lesions independent of its helicase activity, and optimal activation of ATM requires both p53 and BLM helicase activities. (PMID:15539948)
• Data suggest that Nijmegen breakage syndrome 1 (Nbs1) functions in both ATR- (ataxia-telangiectasia and Rad3-related protein) and ataxia telangiectasia mutated protein-dependent signalling. (PMID:15616588)
• not required for HIV-1 derived lentivirus vector integration (PMID:15650165)
• Both 53BP1 and NFBD1 are required for recruitment of ATR to DNA damage sites, as well as for ATR-dependent phosphorylation in response to DNA damage. (PMID:15734998)
• ATRIP is required for ATR accumulation at intranuclear foci induced by DNA damage. (PMID:15743907)
• The ATR protein Deltap53 is an essential element of the ATR-intra-S phase checkpoint. (PMID:16009130)
• regulated degradation of histone mRNAs requires regulator of nonsense transcripts 1 delta helicase, a key regulator of the nonsense-mediated decay pathway, and ATR, a key regulator of the DNA damage checkpoint pathway activated during replication stress (PMID:16086026)
• PP5 plays a critical role in ATR-mediated checkpoint activation (PMID:16260606)
• ATM and Mre11 may stimulate the ATR signaling pathway by converting DNA damage generated by ionizing radiation into structures that recruit and activate ATR (PMID:16431910)
• ATR was indentified as a novel mediator of telomere-dependent senescence in response to interstrand cross-link induced by photoactivated psoralens. (PMID:16436511)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	atr	ENSDARG00000079625
mus_musculus	Atr	ENSMUSG00000032409
rattus_norvegicus	Atr	ENSRNOG00000010027
drosophila_melanogaster	mei-41	FBGN0004367

Paralogs (5): ATM (ENSG00000149311), SMG1 (ENSG00000157106), TRRAP (ENSG00000196367), MTOR (ENSG00000198793), PRKDC (ENSG00000253729)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:108028) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 109 distinct phenotype terms.

Mouse phenotype (MP)	Records
osteoporosis	2
kyphosis	2
decreased hair follicle number	2
decreased brain size	2
decreased body weight	2
abnormal coat/hair pigmentation	2
premature death	2
embryonic lethality between implantation and somite formation, complete penetrance	2
abnormal fontanelle morphology	1
malocclusion	1
abnormal trabecular bone morphology	1
decreased compact bone thickness	1
decreased bone marrow cell number	1
decreased cell proliferation	1
abnormal hair follicle morphology	1
alopecia	1
delayed hair regrowth	1
abnormal hair cycle	1
microcephaly	1
abnormal intestinal epithelium morphology	1
abnormal liver morphology	1
decreased thymocyte number	1
abnormal corpus callosum morphology	1
abnormal cerebral cortex morphology	1
abnormal cerebral cortex lamination	1

+84 more (showing top 25).

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
Oryza sativa Indica Group	A2YH41	99.9%	Diamond
Oryza sativa Japonica Group	Q5Z987	99.9%	Diamond
Cryptococcus deneoformans JEC21	P0CP60	96.7%	Diamond
Cryptococcus deneoformans B-3501A	P0CP61	96.7%	Diamond
Sus scrofa	Q6PQD5	88.4%	Diamond
Caenorhabditis elegans	O01510	74.8%	Diamond
Caenorhabditis briggsae	Q61CW2	74.8%	Diamond
Xenopus laevis	Q9DE14	72.6%	Diamond
Saccharomyces cerevisiae S288C	P32600	68.5%	Diamond
Aspergillus nidulans FGSC A4	Q5BHE2	62.0%	Diamond
Arabidopsis thaliana	Q9FKS4	55.9%	Diamond
Schizosaccharomyces pombe 972h-	O14356	52.1%	Diamond
Nakaseomyces glabratus CBS 138	Q6FRZ9	38.2%	Diamond
Encephalitozoon cuniculi GB-M1	Q8SSE7	34.8%	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
PLS1-AS1	ncRNA	105374136
PLS1	protein-coding	5357
XRN1	protein-coding	54464
GK5	protein-coding	256356
TFDP2	protein-coding	7029

Protein

Protein identifiers

Serine/threonine-protein kinase ATR — Q13535 (reviewed: Q13535)

Alternative names: Ataxia telangiectasia and Rad3-related protein, FRAP-related protein 1

All UniProt accessions (5): A0A590UJ01, D6RFJ6, D6RIG7, Q13535, H0Y8R8

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RBBP8, RPA2, SMC1 and p53/TP53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates ‘Ser-139’ of histone variant H2AX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication. Acts as a regulator of the S-G2 transition by restricting the activity of CDK1 during S-phase to prevent premature entry into G2. Acts as a regulator of the nuclear envelope integrity in response to DNA damage and stress. Acts as a mechanical stress sensor at the nuclear envelope: relocalizes to the nuclear envelope in response to mechanical stress and mediates a checkpoint via phosphorylation of CHEK1. Also promotes nuclear envelope rupture in response to DNA damage by mediating phosphorylation of LMNA at ‘Ser-282’, leading to lamin disassembly. Involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability and catalyzing phosphorylation of LMNA at ‘Ser-395’, priming LMNA for subsequent phosphorylation by CDK1 and micronuclei envelope rupture. The rupture of micronuclear envelope triggers the cGAS-STING pathway thereby activating the type I interferon response and innate immunity. Positively regulates the restart of stalled replication forks following activation by the KHDC3L-OOEP scaffold complex.

Subunit / interactions. Forms a heterodimer with ATRIP, forming the ATR-ATRIP complex. Present in a complex containing ATRIP and RPA-coated single-stranded DNA. Binds to DNA, and to UV-damaged DNA with higher affinity. Interacts with MSH2 and HDAC2. Present in a complex containing CHD4 and HDAC2. Interacts with EEF1E1, the interaction is enhanced by UV irradiation. Interacts with CLSPN and CEP164. Interacts with TELO2 and TTI1. Interacts with BCR-ABL after genotoxic stress. Interacts with UHRF2; this interaction promotes ATR activation. Interacts (when phosphorylated) with TOPBP1; interaction takes place when ATR is autophosphorylated at Thr-1989, leading to ATR activation by TOPBP1.

Subcellular location. Nucleus. Chromosome. Nucleus envelope.

Tissue specificity. Ubiquitous, with highest expression in testis. Isoform 2 is found in pancreas, placenta and liver but not in heart, testis and ovary.

Post-translational modifications. Phosphorylated. Autophosphorylation at Thr-1989 in response to DNA damage promotes interaction with TOPBP1 and activation of ATR.

Disease relevance. Seckel syndrome 1 (SCKL1) [MIM:210600] A rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and intellectual disability. The disease is caused by variants affecting the gene represented in this entry. Cutaneous telangiectasia and cancer syndrome, familial (FCTCS) [MIM:614564] A disease characterized by cutaneous telangiectases in infancy with patchy alopecia over areas of affected skin, thinning of the lateral eyebrows, and mild dental and nail anomalies. Affected individuals are at increased risk of developing oropharyngeal cancer, and other malignancies have been reported as well. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Serine/threonine-protein kinase activity is directly stimulated by TOPBP1. ATR kinase activity is also directly activated by ETAA1, independently of TOPBP1. Activated by DNA and inhibited by BCR-ABL oncogene. Slightly activated by ATRIP. Inhibited by caffeine, wortmannin and LY294002.

Similarity. Belongs to the PI3/PI4-kinase family. ATM subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13535-1	1	yes
Q13535-2	2
Q13535-3	3

RefSeq proteins (2): NP_001175, NP_001341508 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000403	PI3/4_kinase_cat_dom	Domain
IPR003151	PIK-rel_kinase_FAT	Domain
IPR003152	FATC_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011989	ARM-like	Homologous_superfamily
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR012993	UME	Domain
IPR014009	PIK_FAT	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR018936	PI3/4_kinase_CS	Conserved_site
IPR021133	HEAT_type_2	Repeat
IPR036940	PI3/4_kinase_cat_sf	Homologous_superfamily
IPR050517	DDR_Repair_Kinase	Family
IPR056802	ATR-like_M-HEAT	Domain
IPR056803	ATR-like_N-HEAT	Domain
IPR057564	HEAT_ATR	Domain

Pfam: PF00454, PF02259, PF02260, PF08064, PF23593, PF25030, PF25032

Enzyme classification (BRENDA)

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

Catalyzed reactions (Rhea)

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (152 total): helix 76, strand 21, sequence variant 21, turn 11, modified residue 4, splice variant 4, mutagenesis site 4, region of interest 4, domain 3, repeat 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

23 structures by resolution:

PDB	Title	Method	Resolution (Å)
9ZCY	Cryo-EM structure of apo-ATR-ATRIP	ELECTRON MICROSCOPY	2.5
23EW	Cryo-EM structure of human ATR-ATRIP complex with Berzosertib	ELECTRON MICROSCOPY	2.7
23FC	Cryo-EM structure of human ATR-ATRIP complex with ATPgammaS and Chk1	ELECTRON MICROSCOPY	2.7
9L40	kinase of ATR bound VE-822 state	ELECTRON MICROSCOPY	2.87
13DE	Cryo-EM structure of ATR-ATRIP-ETAA1 AAD (S95D/S111D)	ELECTRON MICROSCOPY	2.9
23FE	Cryo-EM structure of human ATR-ATRIP complex with ATPgammaS, Chk1 and ETAA1	ELECTRON MICROSCOPY	2.9
23FB	Cryo-EM structure of human ATR-ATRIP complex with ATPgammaS	ELECTRON MICROSCOPY	3
9ZD3	Cryo-EM structure of ATR-ATRIP-ETAA1 AAD	ELECTRON MICROSCOPY	3
23FA	Cryo-EM structure of human ATR-ATRIP complex with Gartisertib	ELECTRON MICROSCOPY	3.1
23EX	Cryo-EM structure of human ATR-ATRIP complex with Ceralasertib	ELECTRON MICROSCOPY	3.2
23EY	Cryo-EM structure of human ATR-ATRIP complex with Elimusertib	ELECTRON MICROSCOPY	3.2
9L4B	Kinase domain of ATR bound with RP-3500	ELECTRON MICROSCOPY	3.2
9ZD1	Cryo-EM structure of ATR-ATRIP-TOPBP1 AAD	ELECTRON MICROSCOPY	3.2
9ZD4	Cryo-EM structure of symmetric class of ATR-ATRIP-ETAA1 AAD	ELECTRON MICROSCOPY	3.3
26ZN	Cryo-EM structure of human phosphorylate ATR-ATRIP complex with ATPgammaS	ELECTRON MICROSCOPY	3.5
23FD	Cryo-EM structure of human ATR-ATRIP complex with ATPgammaS, Chk1 and TopBp1	ELECTRON MICROSCOPY	3.6
9L4D	ATR-ATRIP bound with RP-3500	ELECTRON MICROSCOPY	3.79
9L43	ATR Spiral -ATRIP bound with VE-822	ELECTRON MICROSCOPY	3.83
9L45	ATR-ATRIP bound with VE-822	ELECTRON MICROSCOPY	3.95
9L4C	ATR Spiral -ATRIP bound with RP-3500	ELECTRON MICROSCOPY	4.06
5YZ0	Cryo-EM Structure of human ATR-ATRIP complex	ELECTRON MICROSCOPY	4.7
9L4F	ATR-ATRIP bound with ATPgammaS	ELECTRON MICROSCOPY	6.22
9L46	ATR-ATRIP-bound with AMP-PNP	ELECTRON MICROSCOPY	6.29

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13535-F1	76.87	0.07

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IF uncertain

Functional residue map

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

Post-translational modifications (4)

Type	Positions
Phosphoserine	428, 435, 436
Phosphothreonine	1989

Mutagenesis-validated functional residues (4)

Position	Phenotype
1989	impaired autophosphorylation, leading to decreased activation of atr.
2327	abolishes kinase activity.
2475	abolishes kinase activity; increases sensitivity to ir and impairs translocation to nuclear foci upon dna damage.
2494	abolishes kinase activity; reduces cell viability, augments sensitivity to ir and uv.

Function

Pathways and Gene Ontology

Reactome pathways

11 curated (TAS) of 35; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

35 pathways:

ID	Pathway	Evidence
R-HSA-9709570	Impaired BRCA2 binding to RAD51 ⚕	curated
R-HSA-176187	Activation of ATR in response to replication stress	curated
R-HSA-6783310	Fanconi Anemia Pathway	curated
R-HSA-69473	G2/M DNA damage checkpoint	curated
R-HSA-5685938	HDR through Single Strand Annealing (SSA)	curated
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange	curated
R-HSA-5693607	Processing of DNA double-strand break ends	curated
R-HSA-3371453	Regulation of HSF1-mediated heat shock response	curated
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation	curated
R-HSA-9938024	Somatic hypermutation of immunoglobulin genes	curated
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes	curated
R-HSA-9701190	Defective homologous recombination repair (HRR) due to BRCA2 loss of function ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-9675136	Diseases of DNA Double-Strand Break Repair ⚕	—
R-HSA-9675135	Diseases of DNA repair ⚕	—
R-HSA-1640170	Cell Cycle	—
R-HSA-69620	Cell Cycle Checkpoints	—
R-HSA-3371556	Cellular response to heat stress	—
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-5693532	DNA Double-Strand Break Repair	—
R-HSA-73894	DNA Repair	—
R-HSA-69481	G2/M Checkpoints	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-5685942	HDR through Homologous Recombination (HRR)	—
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	—
R-HSA-5693579	Homologous DNA Pairing and Strand Exchange	—
R-HSA-5693538	Homology Directed Repair	—
R-HSA-1500620	Meiosis	—
R-HSA-1221632	Meiotic synapsis	electronic
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-5633007	Regulation of TP53 Activity	—
R-HSA-1474165	Reproduction	—
R-HSA-3700989	Transcriptional Regulation by TP53	—

MSigDB gene sets: 492 (showing top): PID_FANCONI_PATHWAY, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_POSITIVE_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_POSITIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_MEIOTIC_SYNAPSIS, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_MEMBRANE_DISASSEMBLY

GO Biological Process (28): DNA damage checkpoint signaling (GO:0000077), telomere maintenance (GO:0000723), nucleobase-containing compound metabolic process (GO:0006139), DNA replication (GO:0006260), DNA repair (GO:0006281), double-strand break repair (GO:0006302), DNA damage response (GO:0006974), negative regulation of DNA replication (GO:0008156), response to xenobiotic stimulus (GO:0009410), response to mechanical stimulus (GO:0009612), replication fork processing (GO:0031297), positive regulation of telomere maintenance via telomerase (GO:0032212), cellular response to UV (GO:0034644), interstrand cross-link repair (GO:0036297), positive regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043517), mitotic G2/M transition checkpoint (GO:0044818), response to arsenic-containing substance (GO:0046685), nuclear membrane disassembly (GO:0051081), protein localization to chromosome, telomeric region (GO:0070198), cellular response to gamma radiation (GO:0071480), replicative senescence (GO:0090399), establishment of RNA localization to telomere (GO:0097694), establishment of protein-containing complex localization to telomere (GO:0097695), regulation of cellular response to heat (GO:1900034), positive regulation of telomerase catalytic core complex assembly (GO:1904884), regulation of double-strand break repair (GO:2000779), chromatin remodeling (GO:0006338), regulation of cellular response to stress (GO:0080135)

GO Molecular Function (12): DNA binding (GO:0003677), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), MutLalpha complex binding (GO:0032405), MutSalpha complex binding (GO:0032407), histone H2AXS139 kinase activity (GO:0035979), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (8): nucleus (GO:0005634), nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), chromosome (GO:0005694), PML body (GO:0016605), ATR-ATRIP complex (GO:0070310), site of DNA damage (GO:0090734), chromosome, telomeric region (GO:0000781)

Reactome top-level categories

16 top-level categories:

Category	Pathways
G2/M Checkpoints	2
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	2
Meiosis	1
Cellular response to heat stress	1
Homologous DNA Pairing and Strand Exchange	1
DNA Repair	1
Transcriptional Regulation by TP53	1
Regulation of TP53 Activity	1
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1
Affinity selection of immunoglobulins	1
Reproduction	1
Cell Cycle	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Generic Transcription Pathway	1

GO top-level categories

59 GO namespaces:

Category	Terms
DNA metabolic process	3
DNA repair	2
response to chemical	2
protein kinase activity	2
mismatch repair complex binding	2
cellular anatomical structure	2
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
telomere organization	1
primary metabolic process	1
DNA biosynthetic process	1
DNA damage response	1
cellular response to stress	1
DNA replication	1
regulation of DNA replication	1
negative regulation of DNA metabolic process	1
response to external stimulus	1
response to abiotic stimulus	1
DNA-templated DNA replication maintenance of fidelity	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomerase	1
positive regulation of telomere maintenance via telomere lengthening	1
positive regulation of DNA biosynthetic process	1
response to UV	1
cellular response to light stimulus	1
DNA damage response, signal transduction by p53 class mediator	1
regulation of DNA damage response, signal transduction by p53 class mediator	1
positive regulation of signal transduction by p53 class mediator	1
mitotic cell cycle checkpoint signaling	1
negative regulation of G2/M transition of mitotic cell cycle	1
membrane disassembly	1
nuclear membrane organization	1
protein localization to chromosome	1
response to gamma radiation	1
cellular response to ionizing radiation	1
nucleic acid binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
protein serine/threonine kinase activity	1
histone H2AX kinase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nucleus	1
endomembrane system	1
organelle envelope	1
nuclear lumen	1
intracellular membraneless organelle	1
nuclear body	1
nuclear protein-containing complex	1
chromosome	1
chromosomal region	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 23 of 48 annotations. The rest are phylogenetic / computational / electronic (IEA).

23 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage checkpoint signaling	BP	direct assay
DNA damage response	BP	direct assay
cellular response to UV	BP	mutant phenotype
cellular response to gamma radiation	BP	direct assay
double-strand break repair	BP	direct assay
establishment of RNA localization to telomere	BP	mutant phenotype
mitotic G2/M transition checkpoint	BP	direct assay
negative regulation of DNA replication	BP	mutant phenotype
nuclear membrane disassembly	BP	direct assay
positive regulation of DNA damage response, signal transduction by p53 class mediator	BP	direct assay
positive regulation of telomerase catalytic core complex assembly	BP	mutant phenotype
protein localization to chromosome, telomeric region	BP	mutant phenotype
replicative senescence	BP	mutant phenotype
response to mechanical stimulus	BP	direct assay
PML body	CC	direct assay
nuclear envelope	CC	direct assay
nucleoplasm	CC	direct assay
site of DNA damage	CC	direct assay
MutLalpha complex binding	MF	direct assay
MutSalpha complex binding	MF	direct assay
histone H2AXS139 kinase activity	MF	direct assay
protein kinase activity	MF	direct assay
protein serine/threonine kinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,422 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATR	CHEK1	O14757	977
ATR	CHEK2	O96017	973
ATR	RAD9A	Q99638	972
ATR	RAD17	O75943	910
ATR	ATRIP	Q8WXE1	869
ATR	XRCC5	P13010	856
ATR	HUS1	O60921	852
ATR	TOPBP1	Q92547	811
ATR	RAD51	Q06609	800
ATR	RAD50	Q92878	792
ATR	RAD52	P43351	784
ATR	TP53BP1	Q12888	783
ATR	MDC1	Q14676	770
ATR	CDC45	O75419	769
ATR	EXO1	Q9UQ84	769

IntAct

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

16 partners by confidence:

Partner	Interaction type	MIscore	Records
ATRIP	direct interaction	0.890	6
CINP	physical association	0.610	4
CDK9	association	0.560	3
CDC5L	physical association	0.540	3
IKBKG	physical association	0.500	2
CENPF	physical association	0.500	1
TTI1	physical association	0.500	1
AATF	phosphorylation reaction	0.440	1
CHEK1	direct interaction	0.440	1
CREB1	phosphorylation reaction	0.440	1
TP53	phosphorylation reaction	0.440	1
PLEC	physical association	0.400	1
AURKA	association	0.350	1
TIMELESS	association	0.350	1
YBX3	association	0.350	1
DBP	colocalization	0.270	1

BioGRID (1,037 interactions; top human partners by supporting records in a sample of 600 records): ATRIP (Affinity Capture-MS; 25 records), NBN (Protein-peptide; 9 records), TOPBP1 (Affinity Capture-Western; 9 records), MSH2 (Affinity Capture-MS; 7 records), RAD17 (Protein-peptide; 7 records), TELO2 (Affinity Capture-Western; 7 records), CHEK1 (Synthetic Lethality; 6 records), PARP1 (Affinity Capture-Western; 6 records), RPA1 (Protein-peptide; 6 records), BSG (Affinity Capture-MS; 5 records), CD274 (Affinity Capture-MS; 5 records), ETAA1 (Affinity Capture-MS; 5 records), TP53 (Synthetic Growth Defect; 5 records), BRCA1 (Reconstituted Complex; 4 records), CHD4 (Affinity Capture-MS; 4 records)

SIGNOR signaling

showing 45 of 77 signaling interactions:

A	Effect	B	Mechanism
ATR	“up-regulates activity”	BRCA1	phosphorylation
ATR	“up-regulates activity”	RAD17	phosphorylation
ATR	“up-regulates quantity by stabilization”	TP53	phosphorylation
ATR	“down-regulates activity”	MDM2	phosphorylation
ATR	down-regulates	CREB1	phosphorylation
ATR	unknown	MCM2	phosphorylation
ATR	up-regulates	ATRIP	phosphorylation
ATR	up-regulates	CDS1
ATR	up-regulates	CHEK1	phosphorylation
CDKN2A	“up-regulates activity”	ATR	phosphorylation
ATR	up-regulates	XPA	phosphorylation
ATR	up-regulates	PRKDC	phosphorylation
ATR	up-regulates	FANCD2	phosphorylation
ATR	“up-regulates activity”	ATM	phosphorylation
ATR	up-regulates	NBN	phosphorylation
ATR	down-regulates	PI4K2A
ABL1	up-regulates	ATR	phosphorylation
ATR	up-regulates	MCM4	phosphorylation
ATR	up-regulates	MCM6	phosphorylation
ATR	up-regulates	POLH	phosphorylation
MUTYH	up-regulates	ATR	binding
ATR	down-regulates	DBF4	phosphorylation
ATR	up-regulates	FANCA	phosphorylation
ATR	unknown	RPA2	phosphorylation
ATR	up-regulates	RBBP8	phosphorylation
ATR	up-regulates	BRCA1	phosphorylation
ATR	up-regulates	XPC	binding
DNA_damage	up-regulates	ATR
ATR	“up-regulates activity”	XPA	phosphorylation
ATR	up-regulates	KMT2A	phosphorylation
ATR	“up-regulates activity”	WDHD1	phosphorylation
ATR	“up-regulates activity”	XRCC3	phosphorylation
“BRCA1-B complex”	“up-regulates activity”	ATR	binding
TOPBP1	“up-regulates activity”	ATR	binding
ATR	“up-regulates activity”	CCAR2	phosphorylation
ATR	“up-regulates quantity by stabilization”	USP20	phosphorylation
ATR	“up-regulates activity”	MCC	phosphorylation
ATR	“down-regulates activity”	SMARCAL1	phosphorylation
ATR	“down-regulates activity”	SIAH1	phosphorylation
ATR	“down-regulates quantity by destabilization”	WRN	phosphorylation
ATR	“up-regulates quantity by stabilization”	KIFC1	phosphorylation
ATR	“down-regulates activity”	PARP1	phosphorylation
ATR	“down-regulates quantity”	WRN	phosphorylation
ATR	“up-regulates activity”	AKAP12	phosphorylation
ATR	“down-regulates activity”	USP20	phosphorylation

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
★ ATR-HDAC2-CHD4 complex	3	ATR, CHD4, HDAC2
ATR-ATRIP-TIM complex	3	ATR, ATRIP, TIMELESS
★ ATR-HDAC2 complex	2	ATR, HDAC2
ATR-ATRIP complex	2	ATR, ATRIP

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
DNA repair	6	23.9×	3e-05

Disease & clinical

Genetic variants

Variant evidence for ATR: 4,233 ClinVar records (140 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

4,233 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	93
Likely pathogenic	47
Uncertain significance	2232
Likely benign	1574
Benign	84

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 140 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1069016	NM_001184.4(ATR):c.5851C>T (p.Arg1951Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
2716985	NM_001184.4(ATR):c.3409C>T (p.Gln1137Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2851856	NM_001184.4(ATR):c.2669T>G (p.Leu890Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
632402	NM_001184.4(ATR):c.2634-1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
959203	NM_001184.4(ATR):c.2533-1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
2712677	NM_001184.4(ATR):c.7042-1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
4081197	NM_001184.4(ATR):c.5261_5264del (p.Thr1754fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
156536	NM_001184.4(ATR):c.3477G>T (p.Met1159Ile)	Pathogenic	criteria provided, single submitter	2
210488	NM_001184.4(ATR):c.4641+1G>T	Pathogenic	criteria provided, single submitter	1
835020	NM_001184.4(ATR):c.1361del (p.Val454fs)	Pathogenic	criteria provided, single submitter	1
871313	NM_001184.4(ATR):c.6687+2T>C	Pathogenic	criteria provided, single submitter	1
916471	NM_001184.4(ATR):c.979_980del (p.Val327fs)	Pathogenic	criteria provided, single submitter	1
1072254	NM_001184.4(ATR):c.4915_4918dup (p.Thr1640fs)	Pathogenic	criteria provided, single submitter	1
1076365	NM_001184.4(ATR):c.529C>T (p.Arg177Ter)	Pathogenic	criteria provided, single submitter	1
1076685	NM_001184.4(ATR):c.5563del (p.His1855fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ATR’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

AlphaMissense

5,611 missense substitutions predicted likely pathogenic (of 17,471 scored), across 1,545 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
M2636	9	0.979	0.997
M2339	9	0.960	0.996
H2477	8	0.999	0.999
N2480	8	0.999	1.000
D2494	8	0.999	1.000
D2330	8	0.998	1.000
D2335	8	0.998	1.000
D2475	8	0.998	1.000
D2331	8	0.995	0.999
D2560	8	0.995	0.999
D1415	8	0.993	0.999
F2499	8	0.993	0.999
H2492	8	0.988	0.998
F2513	8	0.981	0.998
F2557	8	0.977	0.995
F2505	8	0.974	0.996
D1365	8	0.972	0.993
F1511	8	0.964	0.995
D1071	8	0.959	0.992
D1687	8	0.958	0.988

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

5 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.47e-05
Ovary Serous Cystadenocarcinoma (validation)	unfavorable	0.000107
Thyroid Carcinoma (TCGA)	unfavorable	0.000148
Stomach Adenocarcinoma (TCGA)	unfavorable	0.000226
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.0004

Disease associations

OMIM: gene MIM:601215 | disease phenotypes: MIM:210600, MIM:614564, MIM:122470

GenCC curated gene-disease

5 curated gene-disease records:

Disease	Classification	Inheritance	Records
Seckel syndrome 1	Definitive	Autosomal recessive	4
sarcoma	Moderate	Autosomal dominant
familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome	Moderate	Autosomal dominant	3
Seckel syndrome	Supportive	Autosomal recessive
familial prostate carcinoma	Limited	Autosomal dominant

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
DDG2P	green
Fetal anomalies	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Severe microcephaly	green
Cerebral vascular malformations	amber
Clefting	amber
Paediatric disorders	amber
Sarcoma susceptibility	amber
Vascular skin disorders	amber

Mondo (8): Seckel syndrome 1 (MONDO:0008869), familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (MONDO:0013806), hereditary neoplastic syndrome (MONDO:0015356), Cornelia de Lange syndrome 1 (MONDO:0007387), hereditary breast ovarian cancer syndrome (MONDO:0003582), familial prostate carcinoma (MONDO:0023122), sarcoma (MONDO:0005089), Seckel syndrome (MONDO:0019342)

Orphanet (5): Seckel syndrome (Orphanet:808), Inherited cancer-predisposing syndrome (Orphanet:140162), Familial cutaneous telangiectasia and oropharyngeal cancer predisposition syndrome (Orphanet:313846), Cornelia de Lange syndrome (Orphanet:199), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D012509	Sarcoma	C04.557.450.795

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL3885635 (PROTEIN FAMILY), CHEMBL4106138 (PROTEIN COMPLEX), CHEMBL5024 (SINGLE PROTEIN), CHEMBL5739546 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066136 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066578 (PROTEIN COMPLEX)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the ATR protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

4 curated-mechanism drugs:

Drug	Modality	Max phase
CERALASERTIB	Small molecule	3
BERZOSERTIB	Small molecule	2
ELIMUSERTIB	Small molecule	1
M4344	Small molecule	1

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 12,756 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

8 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL4285417	CERALASERTIB	3	1,563
CHEMBL1879463	DACTOLISIB	3	8,349
CHEMBL3989870	BERZOSERTIB	2	1,341
CHEMBL5095260	CAMONSERTIB	2	183
CHEMBL5314933	TUVUSERTIB	2	58
CHEMBL4647810	ELIMUSERTIB	1	316
CHEMBL4650286	M4344	1	549
CHEMBL551064	AEW-541	1	397

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — ATR subfamily

Most potent curated ligand interactions (13 total), top 13:

Ligand	Action	Affinity	Parameter
camonsertib	Inhibition	10.66	pKi
gartisertib	Inhibition	9.82	pKi
berzosertib	Inhibition	9.7	pKi
ceralasertib	Inhibition	9.0	pIC50
gavapsertib	Inhibition	8.7	pIC50
AZ20	Inhibition	8.3	pIC50
elimusertib	Inhibition	8.15	pIC50
tuvusertib	Inhibition	8.0	pKi
VE-821	Inhibition	7.89	pKi
mosipasertib	Inhibition	7.7	pIC50
dactolisib	Inhibition	7.68	pIC50
alnodesertib	Inhibition	7.3	pIC50
BAY-8400	Inhibition	6.4	pIC50

Binding affinities (BindingDB)

2994 measured of 3712 human assays (3716 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL3355476	IC50	0.1 nM
3-[3-[4-[dideuterio(methylamino)methyl]phenyl]isoxazol-5-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine	IC50	0.2 nM
US10392376, Example 40b	IC50	0.3 nM	US-10392376: Heterocyclic inhibitors of ATR kinase
1-Methyl-7-(3-methyl-3H-imidazol-4-yl)-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine	IC50	0.3 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
(1R,5S)-3-[6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-5-yl)pyrazolo[5,4-b]pyridin-4-yl]-8-oxabicyclo[3.2.1]octan-3-ol	IC50	0.33 nM	US-20250066350: AROMATIC HETEROCYCLE-SUBSTITUTED COMPOUNDS, AND PREPARATION METHOD THEREFOR AND USE THEREOF
US10392376, Example 44b	IC50	0.4 nM	US-10392376: Heterocyclic inhibitors of ATR kinase
US10392376, Example 86	IC50	0.4 nM	US-10392376: Heterocyclic inhibitors of ATR kinase
cyclopropyl-methyl-[2-(2-methylbenzimidazol-1-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]imino-oxo-lambda6-sulfane	IC50	0.4 nM	US-11434233: Heterocyclic inhibitors of ATR kinase
(3R)-3-Methyl-4-[1-methyl-7-(4-methylpyrimidin-5-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine	IC50	0.4 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
5-[(3R)-3-fluoro-2,2-dimethyl-1,1-dioxo-3H-1-benzothiophen-5-yl]-3-[3-[4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]pyrazin-2-amine	IC50	0.41 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
[2-[2-(fluoromethyl)benzimidazol-1-yl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]imino-dimethyl-oxo-lambda6-sulfane	IC50	0.5 nM	US-10392376: Heterocyclic inhibitors of ATR kinase
CHEMBL4210045	IC50	0.5 nM
(3R)-3-Methyl-4-[7-(2-methylphenyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine	IC50	0.5 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
3-[3-[4-[(3R)-morpholin-3-yl]phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	KI	0.503 nM	US-20130089624: Compounds Useful as Inhibitors of ATR Kinase
N,N-dimethyl-7-[(3R)-3-methylmorpholin-4-yl]-10-(1H-pyrazol-5-yl)-3,8,10,11-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2(6),4,7,11-pentaene-3-sulfonamide	IC50	0.51 nM	US-20240025899: TRIHETEROCYCLIC DERIVATIVE, AND PHARMACEUTICAL COMPOSITION AND APPLICATION THEREOF
5-(5-amino-6-(5-(4-((1-methylpiperidin-4-yl)amino)methyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-3-fluoro-2,2-dimethyl-2,3-dihydrobenzo[b]thiophene 1,1-dioxide 36	IC50	0.57 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine	IC50	0.6 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
7-[2-(2-Fluoro-ethyl)-2H-pyrazol-3-yl]-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine	IC50	0.6 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
(3R)-3-Methyl-4-[1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine	IC50	0.6 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
(3R)-3-methyl-4-(3-methylsulfonyl-10-pyrazolidin-3-yl-3,8,10,11-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-7-yl)morpholine	IC50	0.69 nM	US-20240025899: TRIHETEROCYCLIC DERIVATIVE, AND PHARMACEUTICAL COMPOSITION AND APPLICATION THEREOF
US10392376, Example 38b	IC50	0.7 nM	US-10392376: Heterocyclic inhibitors of ATR kinase
1-(4-(5-(3-amino-6-(4-(cyclopropylsulfonyl)phenyl)pyrazin-2-yl)isoxazol-3-yl)benzyl)guanidine dihydrochloride 23	IC50	0.7 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine	IC50	0.7 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
1-(4-(5-(3-amino)-6-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-5-yl)pyrazin-2-yl)isoxazol-3-yl)benzyl)guanidine dihydrochloride 27	IC50	0.75 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
3-[4-deuterio-3-[4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-[(3R)-3-fluoro-2,2-dimethyl-1,1-dioxo-3H-1-benzothiophen-5-yl]pyrazin-2-amine	IC50	0.75 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
5-(5-amino-6-(5-(4-((methylamino)methyl)phenyl)-1,3,4-thiadiazol-2-yl)pyrazin-2-yl)-3-fluoro-2,2-dimethyl-2,3-dihydrobenzo[b]thiophene 1,1-dioxide 37	IC50	0.77 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
US10392376, Example 41b	IC50	0.8 nM	US-10392376: Heterocyclic inhibitors of ATR kinase
methyl-[2-(2-methylbenzimidazol-1-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]imino-(oxetan-3-yl)-oxo-lambda6-sulfane	IC50	0.8 nM	US-11434233: Heterocyclic inhibitors of ATR kinase
2-methyl-2-[6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-5-yl)pyrazolo[5,4-b]pyridin-4-yl]propanenitrile	IC50	0.8 nM	US-12264155: Compounds, pharmaceutical compositions, and methods of preparing compounds and of their use as ATR kinase inhibitors
5-((R)-3-Methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine	IC50	0.8 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-7-(2-methyl-pyridin-3-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine	IC50	0.8 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
7-(6-Methanesulfonyl-2-methyl-pyridin-3-yl)-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine	IC50	0.8 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
7-(1-Methanesulfonyl-cyclopropyl)-1-methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine	IC50	0.8 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
1-Methyl-5-((R)-3-methyl-morpholin-4-yl)-3-(2H-pyrazol-3-yl)-7-(tetrahydro-pyran-3-yl)-1H-pyrazolo[4,3-b]pyridine	IC50	0.8 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
4-[1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-2H-1lambda6-thiopyran-1,1-dione	IC50	0.8 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
1-(4-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)isoxazol-3-yl)-3,5-difluorobenzyl)guanidine dihydrochloride 11	IC50	0.82 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
1-(4-(5-(3-amino-6-(4-isopropylsulfonyl)phenyl)pyrazin-2-yl)isoxazol-3-yl)-3-fluorobenzyl)guanidine dihydrochloride 4	IC50	0.83 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
5-[(3R)-3-fluoro-2,2-dimethyl-1,1-dioxo-3H-1-benzothiophen-5-yl]-3-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine	IC50	0.83 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
US10392376, Example 52	IC50	0.9 nM	US-10392376: Heterocyclic inhibitors of ATR kinase
US10392376, Example 95	IC50	0.9 nM	US-10392376: Heterocyclic inhibitors of ATR kinase
CHEMBL4212961	IC50	0.9 nM
(3R)-3-Methyl-4-[3-(3-methyl-1H-pyrazol-5-yl)-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]morpholine	IC50	0.9 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
(3R)-4-[7-(6-Methanesulfonyl-2-methylpyridin-3-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine	IC50	0.9 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
(3R)-4-[7-(1-Methanesulfonylethyl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methylmorpholine	IC50	0.9 nM	US-12371430: 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
5-(5-amino-6-(5-(4-((methylamino)methyl)phenyl)isoxazol-3-yl)pyrazin-2-yl)-3-fluoro-2,2-dimethyl-2,3-dihydrobenzo[b]thiophene 1,1-dioxide 34	IC50	0.92 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
1-(4-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)isoxazol-3-yl)phenyl)-3-methylguanidine dihydrochloride 17	IC50	0.93 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
1-(4-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)isoxazol-3-yl)benzyl)guanidine dihydrochloride 1	IC50	0.97 nM	US-20250026742: COMPOUND AS ATR KINASE INHIBITOR
US10392376, Example 1	IC50	1 nM	US-10392376: Heterocyclic inhibitors of ATR kinase
US10392376, Example 46b	IC50	1 nM	US-10392376: Heterocyclic inhibitors of ATR kinase
(R)-((6-(2-Amino-1H- benzo[d]imidazol-1-yl)-4-(3- methylmorpholino)pyridin-2- yl)imino)dimethyl-lambda6-sulfanone	IC50	1 nM	US-10894052: Heterocyclic inhibitors of ATR kinase

ChEMBL bioactivities

5524 potent at pChembl≥5 of 5571 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.22	Ki	0.06	nM	CERALASERTIB
10.00	IC50	0.1	nM	CHEMBL3355476
9.85	Ki	0.14	nM	CHEMBL4444602
9.83	Ki	0.148	nM	BERZOSERTIB
9.82	IC50	0.15	nM	M4344
9.78	Ki	0.165	nM	BERZOSERTIB
9.77	IC50	0.17	nM	BERZOSERTIB
9.70	IC50	0.2	nM	CHEMBL3355474
9.70	Ki	0.2	nM	BERZOSERTIB
9.68	Ki	0.21	nM	CHEMBL4533440
9.57	Ki	0.27	nM	CHEMBL4443525
9.52	IC50	0.3	nM	CHEMBL3355072
9.52	IC50	0.3	nM	CHEMBL5783158
9.48	IC50	0.33	nM	CAMONSERTIB
9.40	IC50	0.4	nM	CHEMBL3355074
9.40	IC50	0.4	nM	CHEMBL3355475
9.40	IC50	0.4	nM	CHEMBL5786594
9.40	IC50	0.4	nM	CHEMBL6010318
9.30	IC50	0.5	nM	CHEMBL3355069
9.30	IC50	0.5	nM	CHEMBL3355071
9.30	IC50	0.5	nM	CHEMBL3355480
9.30	Ki	0.503	nM	CHEMBL3642117
9.30	IC50	0.5	nM	CHEMBL5775367
9.28	Ki	0.53	nM	CHEMBL4566104
9.22	IC50	0.6	nM	ELIMUSERTIB
9.15	IC50	0.7	nM	CHEMBL5800832
9.12	Ki	0.75	nM	CHEMBL4448538
9.10	IC50	0.8	nM	CHEMBL5567701
9.10	IC50	0.8	nM	CHEMBL5783158
9.10	IC50	0.8	nM	CHEMBL5800499
9.05	IC50	0.9	nM	CAMONSERTIB
9.05	IC50	0.9	nM	CHEMBL5761609
9.05	IC50	0.9	nM	CHEMBL5928836
9.00	IC50	1	nM	CHEMBL3355070
9.00	IC50	1	nM	CHEMBL3355073
9.00	IC50	1	nM	CHEMBL3355473
9.00	IC50	1	nM	CHEMBL4293269
9.00	IC50	1	nM	CHEMBL4288033
9.00	Ki	1	nM	CHEMBL4434665
9.00	Ki	1	nM	CHEMBL4440048
9.00	Ki	1	nM	CHEMBL4467820
9.00	IC50	1	nM	CHEMBL5394792
9.00	IC50	1	nM	CERALASERTIB
9.00	IC50	1	nM	CHEMBL5790125
9.00	IC50	1	nM	CHEMBL5957036
9.00	IC50	1	nM	CHEMBL5829979
9.00	IC50	1	nM	CAMONSERTIB
9.00	IC50	1	nM	CHEMBL5173530
8.96	IC50	1.1	nM	M4344
8.92	IC50	1.2	nM	CHEMBL5417125

PubChem BioAssay actives

710 with measured affinity, of 1367 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[3-[4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	2067683: Inhibition of ATR (unknown origin) by Morrison equation based analysis	ki	<0.0001	uM
(3R)-4-[6-(5-fluoro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-methylimidazo[4,5-c]pyridin-4-yl]-3-methylmorpholine	1177189: Inhibition of human ATR using ATP substrate measured after 3 hrs	ic50	0.0001	uM
imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-lambda6-sulfane	2067683: Inhibition of ATR (unknown origin) by Morrison equation based analysis	ki	0.0001	uM
3-[3-[4-[(oxan-4-ylamino)methyl]phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555163: Inhibition of recombinant human full-length N-terminal Flag epitope-tagged ATR expressed in HEK293T cells using ASELPASQPQPFSAKKK peptide as substrate measured after 24 hrs in presence of [gamma-33P] ATP by microbeta liquid scintillation counting analysis	ki	0.0001	uM
2-amino-6-fluoro-N-[5-fluoro-4-[4-[4-(oxetan-3-yl)piperazine-1-carbonyl]piperidin-1-yl]-3-pyridinyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1872291: Binding affinity to ATR (unknown origin) assessed as inhibition constant	ki	0.0001	uM
(3R)-3-methyl-4-[1-[(1R)-1-methylsulfonylethyl]-6-(1H-pyrrolo[2,3-c]pyridin-4-yl)imidazo[4,5-c]pyridin-4-yl]morpholine	1177189: Inhibition of human ATR using ATP substrate measured after 3 hrs	ic50	0.0002	uM
3-[3-[4-(ethylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555163: Inhibition of recombinant human full-length N-terminal Flag epitope-tagged ATR expressed in HEK293T cells using ASELPASQPQPFSAKKK peptide as substrate measured after 24 hrs in presence of [gamma-33P] ATP by microbeta liquid scintillation counting analysis	ki	0.0002	uM
(6R)-6-methyl-3-(4-methylsulfonylphenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine	1177170: Inhibition of ATR (unknown origin) using Avi-tagged protein substrate by alphascreen assay	ic50	0.0003	uM
(1R,5S)-3-[6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-5-yl)pyrazolo[5,4-b]pyridin-4-yl]-8-oxabicyclo[3.2.1]octan-3-ol	2067712: Inhibition of ATR in gemcitabine-stimulated human LoVo cells assessed as decrease in CHK1 phosphorylation at Ser345 residue	ic50	0.0003	uM
3-[3-[4-(aminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555163: Inhibition of recombinant human full-length N-terminal Flag epitope-tagged ATR expressed in HEK293T cells using ASELPASQPQPFSAKKK peptide as substrate measured after 24 hrs in presence of [gamma-33P] ATP by microbeta liquid scintillation counting analysis	ki	0.0003	uM
(6R)-5-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-methyl-3-(1-methylsulfonylpiperidin-4-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine	1177170: Inhibition of ATR (unknown origin) using Avi-tagged protein substrate by alphascreen assay	ic50	0.0004	uM
(3R)-3-methyl-4-[1-methyl-6-(1H-pyrrolo[2,3-c]pyridin-4-yl)imidazo[4,5-c]pyridin-4-yl]morpholine	1177189: Inhibition of human ATR using ATP substrate measured after 3 hrs	ic50	0.0004	uM
N,N-dimethyl-4-[6-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl]benzenesulfonamide	1177170: Inhibition of ATR (unknown origin) using Avi-tagged protein substrate by alphascreen assay	ic50	0.0005	uM
(3R)-3-methyl-4-[1-methyl-6-(1H-pyrrolo[2,3-d]pyridazin-4-yl)imidazo[4,5-c]pyridin-4-yl]morpholine	1177189: Inhibition of human ATR using ATP substrate measured after 3 hrs	ic50	0.0005	uM
3-[3-[4-[(1R)-1-aminoethyl]phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555163: Inhibition of recombinant human full-length N-terminal Flag epitope-tagged ATR expressed in HEK293T cells using ASELPASQPQPFSAKKK peptide as substrate measured after 24 hrs in presence of [gamma-33P] ATP by microbeta liquid scintillation counting analysis	ki	0.0005	uM
N,N-dimethyl-4-[(6R)-6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]benzenesulfonamide	1177170: Inhibition of ATR (unknown origin) using Avi-tagged protein substrate by alphascreen assay	ic50	0.0005	uM
(3R)-3-methyl-4-[4-(2-methylpyrazol-3-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine	2067712: Inhibition of ATR in gemcitabine-stimulated human LoVo cells assessed as decrease in CHK1 phosphorylation at Ser345 residue	ic50	0.0006	uM
2-methyl-2-[6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-5-yl)pyrazolo[5,4-b]pyridin-4-yl]propanenitrile	2067684: Inhibition of ATR in human HeLa S3 cells assessed as decrease in CHK1 phosphorylation at Ser345 residue pretreated for 20 mins followed by gemcitabine stimulation for 3.5 to 4 hrs by AlphaScreen SurFire assay	ic50	0.0008	uM
3-[3-[2-chloro-4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555163: Inhibition of recombinant human full-length N-terminal Flag epitope-tagged ATR expressed in HEK293T cells using ASELPASQPQPFSAKKK peptide as substrate measured after 24 hrs in presence of [gamma-33P] ATP by microbeta liquid scintillation counting analysis	ki	0.0008	uM
N,N-dimethyl-4-[5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]benzenesulfonamide	1177170: Inhibition of ATR (unknown origin) using Avi-tagged protein substrate by alphascreen assay	ic50	0.0010	uM
(6R)-6-methyl-3-(1-methylsulfonylpiperidin-4-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine	1177170: Inhibition of ATR (unknown origin) using Avi-tagged protein substrate by alphascreen assay	ic50	0.0010	uM
(3R)-4-[6-(1H-indol-4-yl)-1-(methylsulfonylmethyl)imidazo[4,5-c]pyridin-4-yl]-3-methylmorpholine	1177189: Inhibition of human ATR using ATP substrate measured after 3 hrs	ic50	0.0010	uM
N-methyl-1-[(10S,14R)-14-methyl-6-(2-methylsulfonylpropan-2-yl)-8,12-dioxa-1,3,5-triazatricyclo[8.4.0.02,7]tetradeca-2,4,6-trien-4-yl]benzimidazol-2-amine	1410235: Inhibition of recombinant human full length ATR/ATRIP expressed in mammalian expression system using c-Myc-tagged p53 as substrate incubated for 15 mins followed by substrate addition measured after 25 to 35 mins by TR-FRET assay	ic50	0.0010	uM
N-methyl-4-[(10S,14R)-14-methyl-6-(2-methylsulfonylpropan-2-yl)-8,12-dioxa-1,3,5-triazatricyclo[8.4.0.02,7]tetradeca-2,4,6-trien-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-amine	1410235: Inhibition of recombinant human full length ATR/ATRIP expressed in mammalian expression system using c-Myc-tagged p53 as substrate incubated for 15 mins followed by substrate addition measured after 25 to 35 mins by TR-FRET assay	ic50	0.0010	uM
2-[(10S,14R)-14-methyl-4-[5-(methylamino)-1H-pyrrolo[2,3-b]pyridin-4-yl]-8,12-dioxa-1,3,5-triazatricyclo[8.4.0.02,7]tetradeca-2,4,6-trien-6-yl]propan-2-ol	1410235: Inhibition of recombinant human full length ATR/ATRIP expressed in mammalian expression system using c-Myc-tagged p53 as substrate incubated for 15 mins followed by substrate addition measured after 25 to 35 mins by TR-FRET assay	ic50	0.0010	uM
N-ethyl-4-[(10S,14R)-14-methyl-6-(2-methylsulfonylpropan-2-yl)-8,12-dioxa-1,3,5-triazatricyclo[8.4.0.02,7]tetradeca-2,4,6-trien-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-amine	1410235: Inhibition of recombinant human full length ATR/ATRIP expressed in mammalian expression system using c-Myc-tagged p53 as substrate incubated for 15 mins followed by substrate addition measured after 25 to 35 mins by TR-FRET assay	ic50	0.0010	uM
cyclopropyl-methyl-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]imino-oxo-lambda6-sulfane	2218851: Inhibition of human full-length FLAG-TEV-tagged ATR/His6-tagged ATRIP expressed in HEK293 cells using FAM-labeled RAD17 peptide and ATP as substrate preincubated with enzyme for 30 mins followed by incubation with peptide for 6 hrs by caliper-based assay	ic50	0.0010	uM
1-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-2-yl]benzimidazol-2-amine	1423055: Inhibition of ATR in human HeLa cell nuclear extract using GST-fused p53N66 as substrate preincubated for 10 mins followed by ATP addition and measured after 1 hr by ELISA	ic50	0.0010	uM
3-(5-phenyl-1,3,4-thiadiazol-2-yl)-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555163: Inhibition of recombinant human full-length N-terminal Flag epitope-tagged ATR expressed in HEK293T cells using ASELPASQPQPFSAKKK peptide as substrate measured after 24 hrs in presence of [gamma-33P] ATP by microbeta liquid scintillation counting analysis	ki	0.0010	uM
3-(3-phenyl-1,2-oxazol-5-yl)-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555163: Inhibition of recombinant human full-length N-terminal Flag epitope-tagged ATR expressed in HEK293T cells using ASELPASQPQPFSAKKK peptide as substrate measured after 24 hrs in presence of [gamma-33P] ATP by microbeta liquid scintillation counting analysis	ki	0.0010	uM
(3R)-3-methyl-4-[1-methyl-7-(2-methylpyrazol-3-yl)-3-(1H-pyrazol-5-yl)pyrazolo[4,5-d]pyrimidin-5-yl]morpholine	2253799: Inhibition of human recombinant ATR incubated for 40 mins by fluorescence based analysis	ic50	0.0010	uM
1-[4-[(3R)-3-methylmorpholin-4-yl]-7-methylsulfonylthieno[3,2-d]pyrimidin-2-yl]benzimidazol-2-amine	1970596: Inhibition of ATR (unknown origin)	ic50	0.0010	uM
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555163: Inhibition of recombinant human full-length N-terminal Flag epitope-tagged ATR expressed in HEK293T cells using ASELPASQPQPFSAKKK peptide as substrate measured after 24 hrs in presence of [gamma-33P] ATP by microbeta liquid scintillation counting analysis	ki	0.0010	uM
3-[3-[4-[(1S)-1-aminoethyl]phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555163: Inhibition of recombinant human full-length N-terminal Flag epitope-tagged ATR expressed in HEK293T cells using ASELPASQPQPFSAKKK peptide as substrate measured after 24 hrs in presence of [gamma-33P] ATP by microbeta liquid scintillation counting analysis	ki	0.0012	uM
5-fluoro-1-[4-[(3R)-3-methylmorpholin-4-yl]-7-methylsulfonylthieno[3,2-d]pyrimidin-2-yl]benzimidazol-2-amine	1970596: Inhibition of ATR (unknown origin)	ic50	0.0012	uM
1-[6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-5-yl)pyrazolo[5,4-b]pyridin-4-yl]cyclohexan-1-ol	2067684: Inhibition of ATR in human HeLa S3 cells assessed as decrease in CHK1 phosphorylation at Ser345 residue pretreated for 20 mins followed by gemcitabine stimulation for 3.5 to 4 hrs by AlphaScreen SurFire assay	ic50	0.0013	uM
2,2,3,3,4,4,5,5,6,6-decadeuterio-1-[6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-5-yl)pyrazolo[5,4-b]pyridin-4-yl]cyclohexan-1-ol	2067684: Inhibition of ATR in human HeLa S3 cells assessed as decrease in CHK1 phosphorylation at Ser345 residue pretreated for 20 mins followed by gemcitabine stimulation for 3.5 to 4 hrs by AlphaScreen SurFire assay	ic50	0.0015	uM
N-methyl-1-[4-[(3R)-3-methylmorpholin-4-yl]-7-methylsulfonylthieno[3,2-d]pyrimidin-2-yl]benzimidazol-2-amine	1970596: Inhibition of ATR (unknown origin)	ic50	0.0015	uM
(3R)-3-methyl-4-[7-methylsulfonyl-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrrolo[2,3-d]pyrimidin-4-yl]morpholine	2086900: Inhibition of ATR/ATRIP (unknown origin) using 5-FAM-AK-17 as substrate preincubated with compound for 10 mins followed by ATP addition and measured after 240 mins by mobility shift assay	ic50	0.0016	uM
(3R)-3-methyl-4-[7-methylsulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolo[2,3-d]pyrimidin-4-yl]morpholine	2086900: Inhibition of ATR/ATRIP (unknown origin) using 5-FAM-AK-17 as substrate preincubated with compound for 10 mins followed by ATP addition and measured after 240 mins by mobility shift assay	ic50	0.0016	uM
7-[(6R)-6-methyl-3-(1-methylsulfonylpiperidin-4-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-1H-imidazo[4,5-b]pyridine	1177170: Inhibition of ATR (unknown origin) using Avi-tagged protein substrate by alphascreen assay	ic50	0.0020	uM
3,3-dimethyl-2-[2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]butan-2-ol	1652460: Inhibition of 5’-TAMRA-labeled tracer 3’,6’-bis(dimethylamino)-N-(4-{[2(1H-indol-4-yl)-6-(morpholin-4-yl)-pyrimidin-4-yl]amino}butyl)-3-oxo-3H-spiro[2-benzofuran-1,9’-xanthene]-5-carboxamide binding to recombinant human full-length N-terminal Flag-tagged ATR expressed in HEK293-6E cells co-expressing human full-length STREP-tagged ATRIP preincubated for 10 mins followed by tracer addition and measured after 30 mins by TR-FRET assay	ic50	0.0020	uM
dimethyl-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]imino-oxo-lambda6-sulfane	2218851: Inhibition of human full-length FLAG-TEV-tagged ATR/His6-tagged ATRIP expressed in HEK293 cells using FAM-labeled RAD17 peptide and ATP as substrate preincubated with enzyme for 30 mins followed by incubation with peptide for 6 hrs by caliper-based assay	ic50	0.0020	uM
(3R)-3-methyl-4-[6-(1-methylsulfonylcyclopropyl)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrimidin-4-yl]morpholine	1423055: Inhibition of ATR in human HeLa cell nuclear extract using GST-fused p53N66 as substrate preincubated for 10 mins followed by ATP addition and measured after 1 hr by ELISA	ic50	0.0020	uM
N-methyl-1-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-2-yl]benzimidazol-2-amine	1423055: Inhibition of ATR in human HeLa cell nuclear extract using GST-fused p53N66 as substrate preincubated for 10 mins followed by ATP addition and measured after 1 hr by ELISA	ic50	0.0020	uM
5-fluoro-1-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-2-yl]benzimidazol-2-amine	1423055: Inhibition of ATR in human HeLa cell nuclear extract using GST-fused p53N66 as substrate preincubated for 10 mins followed by ATP addition and measured after 1 hr by ELISA	ic50	0.0020	uM
3-(5-phenyl-1,2-oxazol-3-yl)-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555163: Inhibition of recombinant human full-length N-terminal Flag epitope-tagged ATR expressed in HEK293T cells using ASELPASQPQPFSAKKK peptide as substrate measured after 24 hrs in presence of [gamma-33P] ATP by microbeta liquid scintillation counting analysis	ki	0.0020	uM
1-[2-(1H-indol-4-yl)-7,7-dimethyl-4-[(3R)-3-methylmorpholin-4-yl]-5H-pyrrolo[3,4-d]pyrimidin-6-yl]ethanone	1979993: Inhibition of ATR (unknown origin) using peptide as substrate preincubated for 10 mins followed by substrate addition by microplate reader analysis	ic50	0.0020	uM
1-[2-(1H-indol-4-yl)-7,7-dimethyl-4-[(3R)-3-methylmorpholin-4-yl]-5H-pyrrolo[3,4-d]pyrimidin-6-yl]propan-1-one	1979993: Inhibition of ATR (unknown origin) using peptide as substrate preincubated for 10 mins followed by substrate addition by microplate reader analysis	ic50	0.0020	uM
4-fluoro-1-[4-[(3R)-3-methylmorpholin-4-yl]-7-methylsulfonylthieno[3,2-d]pyrimidin-2-yl]benzimidazol-2-amine	1970596: Inhibition of ATR (unknown origin)	ic50	0.0020	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects cotreatment, decreases response to substance, affects binding, increases reaction, decreases expression (+7 more)	7
sodium arsenite	affects methylation, decreases expression	5
Caffeine	increases activity, affects cotreatment, increases phosphorylation, increases reaction, decreases activity (+4 more)	5
Tobacco Smoke Pollution	decreases expression, increases expression	5
bisphenol A	decreases methylation, affects cotreatment, increases expression, decreases expression	3
3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide	affects response to substance, decreases phosphorylation, decreases reaction, increases phosphorylation	3
Estradiol	increases expression	3
Cadmium Chloride	increases abundance, increases phosphorylation, increases expression	3
2-chloroethyl ethyl sulfide	increases phosphorylation, affects reaction	2
chromium hexavalent ion	increases activity, affects reaction, increases phosphorylation, increases ubiquitination, increases reaction	2
4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine	increases phosphorylation, decreases activity, increases response to substance, affects cotreatment, decreases reaction	2
Resveratrol	affects cotreatment, decreases reaction, increases activity, increases expression, increases phosphorylation	2
Decitabine	increases activity, affects reaction, increases expression, affects localization, increases phosphorylation (+1 more)	2
Arsenic Trioxide	increases expression, increases reaction, increases activity	2
Acetaminophen	decreases expression, increases expression	2
Cadmium	increases abundance, increases phosphorylation	2
Camptothecin	decreases reaction, increases phosphorylation, decreases response to substance	2
Doxorubicin	decreases phosphorylation, affects expression, affects response to substance	2
Floxuridine	decreases response to substance	2
Hydroxyurea	increases activity, increases phosphorylation, increases reaction, decreases activity, increases response to substance (+1 more)	2
Metribolone	decreases reaction, increases expression, affects binding, increases reaction, increases phosphorylation	2
FR900359	affects phosphorylation	1
prexasertib	affects response to substance, decreases phosphorylation	1
methyleugenol-2’,3’-epoxide	increases phosphorylation	1
3’-oxomethylisoeugenol	increases phosphorylation	1
PF-06840003	decreases expression, decreases reaction	1
ABBV-744	increases phosphorylation	1
INCB057643	decreases phosphorylation, affects cotreatment	1
dicrotophos	decreases expression	1
methyleugenol	increases phosphorylation	1

ChEMBL screening assays

231 unique, capped per target: 226 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3760509	Binding	Activation of ATM/ATR in human HCT116 cells assessed as increase in Chk1 phosphorylation at S345 at 7.5 to 30 uM after 24 hrs by Western blot analysis	Antitumor Activity of Americanin A Isolated from the Seeds of Phytolacca americana by Regulating the ATM/ATR Signaling Pathway and the Skp2-p27 Axis in Human Colon Cancer Cells. — *J Nat Prod*
CHEMBL4612751	Functional	In vivo inhibition of ATR in human SUDHL8 cells harboring ATM K1964E mutant xenografted CB-17 mouse assessed as reduction in ATR phosphorylation at 50 mg/kg, po bid dosed every 3 days followed by 4 days interval	Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models. — *J Med Chem*

Cellosaurus cell lines

32 cell lines: 26 cancer cell line, 4 transformed cell line, 1 finite cell line, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1279	HGC-27	Cancer cell line	Sex unspecified
CVCL_1508	NCI-H1944	Cancer cell line	Female
CVCL_1688	SF126	Cancer cell line	Female
CVCL_1B42	AIK-T4	Transformed cell line	Female
CVCL_2142	NK-92	Cancer cell line	Male
CVCL_2299	ATRFLOX	Cancer cell line	Male
CVCL_6G80	GM18366	Finite cell line	Male
CVCL_6G81	GM18367	Transformed cell line	Male
CVCL_7947	GM847/ATRkd	Transformed cell line	Male
CVCL_A5LZ	U2OS-ATRkd	Cancer cell line	Female

Clinical trials (associated diseases)

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

showing 60 of 599 trials:

NCT	Phase	Status	Title
NCT03144206	Phase 4	ACTIVE_NOT_RECRUITING	Hyperbaric Oxygen Therapy for Soft Tissue Sarcoma Pilot Study
NCT03244020	Phase 4	ENROLLING_BY_INVITATION	LMWH vs Aspirin for VTE Prophylaxis in Orthopaedic Oncology
NCT04033081	Phase 4	ACTIVE_NOT_RECRUITING	Registry of Sarcoma Patients Treated With Permanently Implantable LDR CivaSheet®
NCT07802847	Phase 4	NOT_YET_RECRUITING	Innovative and Cooperative Pathway Integrating Oncogeriatric, Pharmaceutical and Pharmacological Follow-up in Elderly Patients.
NCT02562170	Phase 4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00014638	Phase 4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	Phase 4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	Phase 4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	Phase 4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	Phase 4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	Phase 4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	Phase 4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	Phase 4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	Phase 4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	Phase 4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	Phase 4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	Phase 4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	Phase 4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	Phase 4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	Phase 4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	Phase 4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	Phase 4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	Phase 4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	Phase 4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	Phase 4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	Phase 4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	Phase 4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	Phase 4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	Phase 4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	Phase 4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	Phase 4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	Phase 4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	Phase 4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	Phase 4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	Phase 4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	Phase 4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	Phase 4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	Phase 4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	Phase 4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	Phase 4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	Phase 4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	Phase 4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	Phase 4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	Phase 4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer
NCT00754767	Phase 4	TERMINATED	L-Carnitine L-Tartrate in Preventing Peripheral Neuropathy Caused By Chemotherapy in Women With Metastatic Breast Cancer
NCT00756717	Phase 4	COMPLETED	Study Of MK-0752 In Combination With Tamoxifen Or Letrozole to Treat Early Stage Breast Cancer
NCT00766532	Phase 4	COMPLETED	Do Aromatase Inhibitors (AIs) Decrease Intestinal Calcium Absorption?
NCT00768222	Phase 4	COMPLETED	Coated VICRYL* Plus Suture Compared to Chinese Silk in Scheduled Breast Cancer Surgery
NCT00772824	Phase 4	COMPLETED	Study of the Effect of Glutamine Supplementation on Chemotherapy Induced Toxicities in Breast Cancer Patients
NCT00774241	Phase 4	WITHDRAWN	PRIMADOS Study:A Study of Avastin (Bevacizumab) Plus Docetaxel for First Line Treatment of Patients With Metastatic Breast Cancer
NCT00812864	Phase 4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00872859	Phase 4	COMPLETED	The BREASTrial:Breast Reconstruction Evaluation Using Acellular Dermal Matrix as a Sling Trial
NCT00882089	Phase 4	COMPLETED	Use of the Contura™ Catheter in Intermediate-Risk, Pathological Stage 0, I, or II (Up to 3.0 cm) Breast Cancer Patients
NCT00882596	Phase 4	COMPLETED	Use of the Contura™ Catheter to Deliver Accelerated Partial Breast Irradiation to Low-risk Breast Cancer Patients
NCT00904410	Phase 4	COMPLETED	Early Assessment of the Response to Neo-adjuvant Chemotherapy in Breast Cancer Patients With FDG-PET
NCT00912639	Phase 4	UNKNOWN	A Clinical Trial of Paclitaxel Loaded Polymeric Micelle in Patients With Taxane-Pretreated Recurrent Breast Cancer
NCT00912938	Phase 4	UNKNOWN	Evaluate the Relationship of Bone Remodeling Markers for Skeletal Complications in Metastatic Breast Cancer Patients
NCT01035099	Phase 4	COMPLETED	RCT of Fixed vs Titrated Letrozole in Breast Cancer Patient Undergoing IVF
NCT01049295	Phase 4	UNKNOWN	Omega-3 Fatty Acids and Chemotherapy-induced Neuropathy and Inflammation in Breast Cancer
NCT01072318	Phase 4	UNKNOWN	Extended Adjuvant Treatment With Letrozole in Breast Cancer Who Complete 5 Years of Toremifene

Predicted chemistry — Sugi Predict

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