PRKDC

Summary

PRKDC (protein kinase, DNA-activated, catalytic subunit, HGNC:9413) is a protein-coding gene on chromosome 8q11.21, encoding DNA-dependent protein kinase catalytic subunit (P78527). Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. It is a common-essential gene (DepMap: required in 90.5% of cancer cell lines).

This gene encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK). It functions with the Ku70/Ku80 heterodimer protein in DNA double strand break repair and recombination. The protein encoded is a member of the PI3/PI4-kinase family.

Source: NCBI Gene 5591 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe combined immunodeficiency due to DNA-PKcs deficiency (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 4,907 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes — 23 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 90.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_006904

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9413
Approved symbol	PRKDC
Name	protein kinase, DNA-activated, catalytic subunit
Location	8q11.21
Locus type	gene with protein product
Status	Approved
Aliases	DNPK1, p350, DNAPK, XRCC7, DNA-PKcs, DNAPKc, DNA-PKC, p460
Ensembl gene	ENSG00000253729
Ensembl biotype	protein_coding
OMIM	600899
Entrez	5591

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 18 retained_intron, 7 protein_coding

ENST00000314191, ENST00000338368, ENST00000432581, ENST00000521331, ENST00000535375, ENST00000536429, ENST00000536483, ENST00000536710, ENST00000540819, ENST00000541488, ENST00000546304, ENST00000697591, ENST00000697601, ENST00000697602, ENST00000697603, ENST00000697604, ENST00000697605, ENST00000697606, ENST00000697607, ENST00000697608, ENST00000697609, ENST00000697610, ENST00000697611, ENST00000911723, ENST00000911724

RefSeq mRNA: 2 — MANE Select: NM_006904 NM_001081640, NM_006904

CCDS: CCDS75734, CCDS75735

Canonical transcript exons

ENST00000314191 — 86 exons

Exon	Start	End
ENSE00001251756	47893139	47893387
ENSE00003463392	47904869	47904976
ENSE00003464290	47857156	47857299
ENSE00003465720	47898470	47898569
ENSE00003469129	47849154	47849303
ENSE00003469759	47881416	47881520
ENSE00003472060	47927771	47927890
ENSE00003478715	47930672	47930787
ENSE00003480320	47858516	47858635
ENSE00003481049	47915328	47915418
ENSE00003481984	47794290	47794501
ENSE00003482980	47803306	47803480
ENSE00003483488	47918277	47918383
ENSE00003486727	47858849	47858986
ENSE00003490575	47957355	47957431
ENSE00003498493	47885944	47886147
ENSE00003505958	47954338	47954446
ENSE00003507347	47935009	47935058
ENSE00003510207	47783742	47783809
ENSE00003511659	47955874	47955948
ENSE00003514268	47897161	47897294
ENSE00003528470	47860899	47860971
ENSE00003530848	47879491	47879658
ENSE00003534300	47888518	47888650
ENSE00003538011	47933965	47934090
ENSE00003538812	47778459	47778660
ENSE00003539593	47957171	47957263
ENSE00003540807	47836338	47836527
ENSE00003543221	47900373	47900467
ENSE00003546223	47782378	47782598
ENSE00003548623	47854083	47854214
ENSE00003550340	47929092	47929178
ENSE00003555327	47799210	47799390
ENSE00003555461	47839148	47839246
ENSE00003559379	47902569	47902795
ENSE00003564718	47826656	47826861
ENSE00003570797	47959973	47960136
ENSE00003571367	47933020	47933172
ENSE00003571607	47782162	47782254
ENSE00003571745	47943974	47944029
ENSE00003574154	47831814	47831926
ENSE00003574485	47785113	47785317
ENSE00003575796	47789151	47789238
ENSE00003577378	47779004	47779093
ENSE00003577697	47773111	47774377
ENSE00003582287	47855222	47855373
ENSE00003583018	47819402	47819510
ENSE00003584498	47912410	47912562
ENSE00003584655	47817450	47817561
ENSE00003585228	47820719	47820943
ENSE00003585871	47913901	47914064
ENSE00003585917	47852673	47852784
ENSE00003588109	47935732	47935900
ENSE00003591773	47953620	47953719
ENSE00003594290	47862373	47862541
ENSE00003600629	47849379	47849503
ENSE00003603195	47776844	47776983
ENSE00003606681	47864556	47864763
ENSE00003608204	47889014	47889222
ENSE00003609287	47800793	47800986
ENSE00003609866	47890257	47890480
ENSE00003609984	47778728	47778799
ENSE00003610356	47830605	47830736
ENSE00003612241	47953807	47953919
ENSE00003613407	47936353	47936517
ENSE00003614443	47927194	47927353
ENSE00003615365	47828168	47828347
ENSE00003615784	47837212	47837419
ENSE00003618540	47943853	47943883
ENSE00003619555	47929853	47930012
ENSE00003621734	47788906	47789049
ENSE00003627485	47862062	47862127
ENSE00003627756	47798237	47798397
ENSE00003628148	47840016	47840189
ENSE00003636146	47777686	47777874
ENSE00003640090	47863399	47863577
ENSE00003646863	47834196	47834396
ENSE00003651913	47877724	47877851
ENSE00003652630	47859611	47859759
ENSE00003653627	47939551	47939697
ENSE00003669434	47821604	47821792
ENSE00003674052	47943209	47943366
ENSE00003675067	47807137	47807326
ENSE00003676109	47881912	47882097
ENSE00003684631	47823858	47823996
ENSE00003691879	47887547	47887705

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 98.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.9993 / max 567.7366, expressed in 1826 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92988	79.4136	1826
92986	0.3588	185
92974	0.2269	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.64	gold quality
stromal cell of endometrium	CL:0002255	97.52	gold quality
ganglionic eminence	UBERON:0004023	97.23	gold quality
embryo	UBERON:0000922	97.21	gold quality
cortical plate	UBERON:0005343	95.81	gold quality
colonic epithelium	UBERON:0000397	94.57	gold quality
adrenal tissue	UBERON:0018303	94.44	gold quality
oral cavity	UBERON:0000167	94.43	gold quality
left uterine tube	UBERON:0001303	94.02	gold quality
ectocervix	UBERON:0012249	93.98	gold quality
endometrium epithelium	UBERON:0004811	93.75	gold quality
right ovary	UBERON:0002118	93.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.37	gold quality
penis	UBERON:0000989	93.34	gold quality
pigmented layer of retina	UBERON:0001782	93.32	gold quality
retina	UBERON:0000966	93.30	gold quality
body of uterus	UBERON:0009853	93.26	gold quality
skin of leg	UBERON:0001511	93.21	gold quality
left ovary	UBERON:0002119	92.87	gold quality
skin of abdomen	UBERON:0001416	92.77	gold quality
esophagus mucosa	UBERON:0002469	92.73	gold quality
right testis	UBERON:0004534	92.68	gold quality
zone of skin	UBERON:0000014	92.58	gold quality
prefrontal cortex	UBERON:0000451	92.43	gold quality
esophagus	UBERON:0001043	92.40	gold quality
endocervix	UBERON:0000458	92.36	gold quality
gastrocnemius	UBERON:0001388	92.34	gold quality
bone marrow cell	CL:0002092	92.29	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.26	gold quality
vagina	UBERON:0000996	92.25	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-2983	no	4909.79
E-MTAB-6386	no	2773.52
E-CURD-10	no	367.74
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
GREB1
ITGB4
PREX1
ROCK2
UGT2B17

Upstream regulators (CollecTRI, top): AP1, E2F1, ESR1, JUN, MYC, PRDM1

miRNA regulators (miRDB)

54 targeting PRKDC, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 90.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• role for DNA-PK in regulating IRF-3 activity (PMID:11867762)
• DNA-dependent protein kinase suppresses double-strand break-induced and spontaneous homologous recombination (PMID:11904432)
• Roles of DNA-dependent protein kinase and ATM in cell-cycle-dependent radiation sensitivity in human cells. (PMID:12065055)
• results suggest that DNA-PK(CS) brings DNA ends together and then undergoes activation of its kinase, presumably to regulate subsequent steps for processing and ligation of the ends (PMID:12065431)
• phosphorylation at Thr2609, Ser2612, Thr2638 and Thr2647 may play an important role in DNA-PK function. (PMID:12186630)
• DNA-PKcs is autophosphorylated at Thr2609 in vivo in a Ku-dependent manner in response to ionizing radiation (PMID:12231622)
• Autophosphorylation of DNA-PK plays an important regulatory role in DNA double-strand break repair by regulating the assembly and disassembly of the DNA-PK-DNA complex. (PMID:12379113)
• Coordinated assembly of Ku and p460 subunits of the DNA-dependent protein kinase on DNA ends is necessary for XRCC4-ligase IV recruitment (PMID:12547193)
• DNA-PKcs subunit and holoenzyme has a role in the signal transduction of ionizing radiation response (PMID:12672807)
• Chk1 and DNA-PK complex proteins have a role in the repair of double strand breaks (PMID:12756247)
• Autophosphorylation of the catalytic subunit of the DNA-dependent protein kinase is required for efficient end processing during DNA double-strand break repair (PMID:12897153)
• up-regulation of DNA-PK complex protein, especially DNA-PKcs, after radiation treatment correlates to radiation resistance (PMID:14556663)
• DNA-PK can be activated by nucleosomes through the ability of Ku to bind to the ends of nucleosomal DNA, and that the activated DNA-PK is capable of phosphorylating H2AX within the nucleosomes (PMID:14627815)
• working model in which DNA-PK creates a stable molecular bridge between two DNA ends that is remodeled after DNA-PK autophosphorylation (PMID:14654699)
• DNA-PK phosphorylated recombinant NDH II in the presence of RNA (PMID:14704337)
• protein phosphatase 5 interacts with DNA-PKcs and dephosphorylates with surprising specificity at least two functional sites. (PMID:14734805)
• evidence that DNA-PK inhibits AAV integration both in vitro and in vivo (PMID:14766968)
• Data describe a novel pathway of ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) signaling that results in nuclear factor kappaB (NF-kappaB) activation and chemoresistance in response to DNA damage. (PMID:14966265)
• Results show that Ku70/Ku80 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) modulate RAG-mediated cleavage during V(D)J recombination. (PMID:15123719)
• cleaved by picornain 2A during poliovirus infection of HeLa cells (PMID:15163725)
• Autophosphorylation at ABCDE sites thus apparently directs a rearrangement of the DNA-PK complex that ensures access to broken ends and joining steps are coupled together within a synaptic complex, making repair more accurate. (PMID:15258142)
• DNA-PK has a role in the Ser-473 phosphorylation step in the activation of PKB (PMID:15262962)
• DNA-PK has roles in the cellular response to DNA double-strand breaks [review] (PMID:15279776)
• Inhibition of PARP-1 and DNA-dependent protein kinase id a powerful strategy for tumor radiosensitization. (PMID:15286704)
• reduced, not depleted expression of DNA-PK during the mature stages of myeloid differentiation (PMID:15353130)
• DNA-PK autophosphorylation is regulated by MDC1 in response to DNA damage (PMID:15377652)
• These results collectively suggested two pathways for IR-induced phosphorylation of Ser46, i.e., direct phosphorylation by DNA-PK and indirect phosphorylation via ATM. (PMID:15381073)
• DNA-PK, ATM and possibly other kinases implicated in H2AX phosphorylation. (PMID:15389585)
• DNA-PK has a positive role in the regulation of apoptosis in human glioblastomas. (PMID:15493013)
• DNAPK was physically required for the mobilization of the XRCC4-ligase IV complex, and for stable recruitment of XRCC4; phosphorylation of either H2AX or XRCC4 was unnecessary for DNAPK or XRCC4-ligase IV recruitment (PMID:15520013)
• DNA-PK augments ATM and ATR in activation of Chk2 by DNA damage. (PMID:15668230)
• Conserved splice variants of a catalytic subunit of DNA-PK (DNA-PKcs) are expressed predominately in nondividing cells (PMID:15668400)
• DNA-PKcs is preferentially activated by the physiologically relevant DNA replication-associated DSBs at the sites of DNA synthesis (PMID:15677476)
• Using cryo-electron microscopy there was generated an approximately 13 A three-dimensional map of DNA-PKcs, revealing the overall architecture and topology of the 4128 residue polypeptide chain and allowing location of domains (PMID:15698568)
• identification of related, conserved carboxy-terminal motifs in human Nbs1, ATRIP and Ku80 proteins that are required for their interaction with ATM, ATR and DNA-PKcs, respectively (PMID:15758953)
• Artemis:DNA-PKcs nuclease may be important in removing secondary structures that hinder processing of DNA ends during nonhomologous DNA end joining . (PMID:15936993)
• Data show that blockade of epidermal growth factor receptor import into the nucleus also blocks radiation-induced activation of DNA-PK, inhibits DNA repair, and increases radiosensitivity of treated cells. (PMID:16000298)
• Significantly lower DNA-PK activity is associated with uterine cervix and breast cancer (PMID:16000400)
• caspase-dependent cleavage of DNA-PKcs during apoptosis does not contribute to the radiosensitizing effects of MG-132 (PMID:16001975)
• DNA-PK activity is required for the increased expression of H2AX in iradiated cells under hypertonic conditions. (PMID:16046194)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	prkdc	ENSDARG00000075083
mus_musculus	Prkdc	ENSMUSG00000022672
rattus_norvegicus	Prkdc	ENSRNOG00000025028

Paralogs (5): ATM (ENSG00000149311), SMG1 (ENSG00000157106), ATR (ENSG00000175054), TRRAP (ENSG00000196367), MTOR (ENSG00000198793)

Protein

Protein identifiers

DNA-dependent protein kinase catalytic subunit — P78527 (reviewed: P78527)

Alternative names: DNPK1, Ser-473 kinase, p460

All UniProt accessions (4): A0A8V8TMR1, F5GX40, P78527, H0YG84

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. Must be bound to DNA to express its catalytic properties. Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C). Recruited by XRCC5 and XRCC6 to DNA ends and is required to (1) protect and align broken ends of DNA, thereby preventing their degradation, (2) and sequester the DSB for repair by NHEJ. Acts as a scaffold protein to aid the localization of DNA repair proteins to the site of damage. The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion. Also involved in modulation of transcription. As part of the DNA-PK complex, involved in the early steps of ribosome assembly by promoting the processing of precursor rRNA into mature 18S rRNA in the small-subunit processome. Binding to U3 small nucleolar RNA, recruits PRKDC and XRCC5/Ku86 to the small-subunit processome. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates ‘Ser-139’ of histone variant H2AX, thereby regulating DNA damage response mechanism. Phosphorylates ASF1A, DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, FH, SRF, NHEJ1/XLF, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2. Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA. Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. Acts as a regulator of the phosphatidylinositol 3-kinase/protein kinase B signal transduction by mediating phosphorylation of ‘Ser-473’ of protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), promoting their activation. Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 ‘Ser-588’ and increasing CRY1 protein stability, most likely through an indirect mechanism. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway. Also regulates the cGAS-STING pathway by catalyzing phosphorylation of CGAS, thereby impairing CGAS oligomerization and activation. Also regulates the cGAS-STING pathway by mediating phosphorylation of PARP1.

Subunit / interactions. DNA-PK is a heterotrimer of PRKDC and the Ku dimer (composed of XRCC6/Ku70 and XRCC5/Ku86). Formation of this complex may be promoted by interaction with ILF3. Component of the core long-range non-homologous end joining (NHEJ) complex (also named DNA-PK complex) composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF. Additional component of the NHEJ complex includes PAXX. Following autophosphorylation, PRKDC dissociates from DNA. Interacts with DNA-PKcs-interacting protein (KIP) with the region upstream the kinase domain. PRKDC alone also interacts with and phosphorylates DCLRE1C, thereby activating the latent endonuclease activity of this protein. Interacts with C1D. Interacts with TTI1 and TELO2. Interacts with CIB1. Interacts with SETX. Interacts with NR4A3; the DNA-dependent protein kinase complex DNA-PK phosphorylates and activates NR4A3 and prevents NR4A3 ubiquitination and degradation. Interacts with BRAT1. Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA. Interacts with KAT5.

Subcellular location. Nucleus. Nucleolus. Cytoplasm. Cytosol.

Post-translational modifications. Autophosphorylated at two clusters, the T2609 cluster and the S2056 cluster. Autophosphorylated on Ser-2056, Thr-2609, Thr-2638 and Thr-2647. Ser-2056 and Thr-2609 are DNA damage-inducible phosphorylation sites (inducible with ionizing radiation, IR) dephosphorylated by PPP5C. Autophosphorylation induces a conformational change that leads to remodeling of the DNA-PK complex, requisite for efficient end processing and DNA repair. Autophosphorylation in trans within DNA-PK complexes loaded on DNA ends leads to the dissociation of PRKDC from DNA and the transition into the short-range NHEJ complex. Autophosphorylation of the T2609 cluster is required for hematopoietic development and protein synthesis in erythrocytes precursors. S-nitrosylated by GAPDH. Polyubiquitinated by RNF144A, leading to proteasomal degradation.

Disease relevance. Immunodeficiency 26 with or without neurologic abnormalities (IMD26) [MIM:615966] A form of severe combined immunodeficiency characterized by reduced or absent T and B cells, recurrent candidiasis, and lower respiratory tract infections. Some patients show dysmorphic features, severe growth failure, microcephaly, seizures, and impaired neurological functions. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activity seems to be attenuated by autophosphorylation. Binding to the SL1 region of U3 small nucleolar RNA promotes auto-phosphorylation activity. Inhibited by wortmannin.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P78527-1	1	yes
P78527-2	2

RefSeq proteins (2): NP_001075109, NP_008835* (*=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
IPR012582	DNAPKcs_CC3	Domain
IPR014009	PIK_FAT	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR018936	PI3/4_kinase_CS	Conserved_site
IPR036940	PI3/4_kinase_cat_sf	Homologous_superfamily
IPR037706	DNA-PK_dom	Domain
IPR045581	DNAPKcs_CC5	Domain
IPR046803	DNAPKcs_CC1-2	Domain
IPR046804	DNA-PKcs_N	Domain
IPR050517	DDR_Repair_Kinase	Family

Pfam: PF00454, PF02259, PF02260, PF08163, PF19704, PF20500, PF20502

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), 2 shown:

• 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 (519 total): helix 233, strand 110, turn 74, sequence variant 44, modified residue 26, region of interest 9, sequence conflict 6, mutagenesis site 6, repeat 5, domain 3, chain 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

47 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7Z87	ELECTRON MICROSCOPY	2.91
7OTY	ELECTRON MICROSCOPY	2.96
7OTW	ELECTRON MICROSCOPY	2.99
7SGL	ELECTRON MICROSCOPY	3
7K11	ELECTRON MICROSCOPY	3.21
6ZFP	ELECTRON MICROSCOPY	3.24
7OTV	ELECTRON MICROSCOPY	3.24
7K10	ELECTRON MICROSCOPY	3.3
7SU3	ELECTRON MICROSCOPY	3.3
7OTM	ELECTRON MICROSCOPY	3.33
7TYR	ELECTRON MICROSCOPY	3.33
7Z88	ELECTRON MICROSCOPY	3.33
7OTP	ELECTRON MICROSCOPY	3.4
8RD4	ELECTRON MICROSCOPY	3.58
7SUD	ELECTRON MICROSCOPY	3.6
6ZH4	ELECTRON MICROSCOPY	3.62
7K0Y	ELECTRON MICROSCOPY	3.7
7K1J	ELECTRON MICROSCOPY	3.9
7K1N	ELECTRON MICROSCOPY	3.9
6ZHA	ELECTRON MICROSCOPY	3.91
6ZH2	ELECTRON MICROSCOPY	3.92
6ZH6	ELECTRON MICROSCOPY	3.93
9IAX	ELECTRON MICROSCOPY	3.97
7K1K	ELECTRON MICROSCOPY	4.1
6ZH8	ELECTRON MICROSCOPY	4.14
7NFC	ELECTRON MICROSCOPY	4.14
9GD7	ELECTRON MICROSCOPY	4.25
7NFE	ELECTRON MICROSCOPY	4.29
5LUQ	X-RAY DIFFRACTION	4.3
7K19	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

No AlphaFold model available for P78527 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Catalytic / active sites (1): 2020–2021 (cleavage; by caspase-3)

Post-translational modifications (26): 117, 511, 687, 828, 841, 893, 1065, 1209, 1970, 2056, 2259, 2535, 2609, 2612, 2638, 2647, 2789, 3205, 3241, 3260 …

Mutagenesis-validated functional residues (6):

Position	Phenotype
1510	loss of interaction with c1d.
1516–1517	loss of interaction with c1d.
2609	leads to radiation sensitivity and impaired dsb joining. gives rise to reduced phosphorylation; when associated with a-2
2612	reduced phosphorylation; when associated with a-2609.
2638	alleviates phosphorylation, leaves a fully active enzyme with compromised cellular resistance to ionizing radiation with
2647	alleviates phosphorylation, leaves a fully active enzyme with compromised cellular resistance to ionizing radiation with

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-3270619	IRF3-mediated induction of type I IFN
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins

MSigDB gene sets: 618 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_CELL_ACTIVATION, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, MORF_DNMT1, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, E2F_Q4_01, GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT

GO Biological Process (58): maturation of 5.8S rRNA (GO:0000460), telomere maintenance (GO:0000723), somitogenesis (GO:0001756), negative regulation of protein phosphorylation (GO:0001933), activation of innate immune response (GO:0002218), B cell lineage commitment (GO:0002326), immature B cell differentiation (GO:0002327), pro-B cell differentiation (GO:0002328), T cell lineage commitment (GO:0002360), double-strand break repair (GO:0006302), double-strand break repair via nonhomologous end joining (GO:0006303), protein phosphorylation (GO:0006468), DNA damage response (GO:0006974), brain development (GO:0007420), heart development (GO:0007507), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), response to gamma radiation (GO:0010332), telomere capping (GO:0016233), peptidyl-serine phosphorylation (GO:0018105), peptidyl-threonine phosphorylation (GO:0018107), mitotic G1 DNA damage checkpoint signaling (GO:0031571), protein destabilization (GO:0031648), cellular response to insulin stimulus (GO:0032869), T cell differentiation in thymus (GO:0033077), immunoglobulin V(D)J recombination (GO:0033152), T cell receptor V(D)J recombination (GO:0033153), small-subunit processome assembly (GO:0034462), ectopic germ cell programmed cell death (GO:0035234), protein modification process (GO:0036211), regulation of circadian rhythm (GO:0042752), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), innate immune response (GO:0045087), positive regulation of lymphocyte differentiation (GO:0045621), positive regulation of erythrocyte differentiation (GO:0045648), positive regulation of translation (GO:0045727), positive regulation of transcription by RNA polymerase II (GO:0045944), rhythmic process (GO:0048511), regulation of smooth muscle cell proliferation (GO:0048660), regulation of epithelial cell proliferation (GO:0050678)

GO Molecular Function (17): double-stranded DNA binding (GO:0003690), RNA binding (GO:0003723), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), DNA-dependent protein kinase activity (GO:0004677), ATP binding (GO:0005524), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), U3 snoRNA binding (GO:0034511), histone H2AXS139 kinase activity (GO:0035979), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), DNA binding (GO:0003677), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (15): chromosome, telomeric region (GO:0000781), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), nucleolus (GO:0005730), cytosol (GO:0005829), DNA-dependent protein kinase-DNA ligase 4 complex (GO:0005958), membrane (GO:0016020), small-subunit processome (GO:0032040), protein-containing complex (GO:0032991), protein-DNA complex (GO:0032993), DNA-dependent protein kinase complex (GO:0070418), nonhomologous end joining complex (GO:0070419), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	1
STING mediated induction of host immune responses	1
DNA Double-Strand Break Repair	1
Protein ubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein phosphorylation	3
nuclear protein-containing complex	3
B cell differentiation	2
cell fate commitment	2
animal organ development	2
nucleic acid binding	2
protein kinase activity	2
protein serine/threonine kinase activity	2
protein binding	2
nuclear lumen	2
protein-containing complex	2
rRNA processing	1
DNA metabolic process	1
telomere organization	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
regulation of protein phosphorylation	1
negative regulation of protein modification process	1
negative regulation of phosphorylation	1
activation of immune response	1
positive regulation of innate immune response	1
lymphoid progenitor cell differentiation	1
T cell differentiation	1
DNA repair	1
double-strand break repair	1
phosphorylation	1
protein modification process	1
cellular response to stress	1
central nervous system development	1
head development	1
circulatory system development	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
response to ionizing radiation	1
telomere maintenance	1
peptidyl-serine modification	1

Protein interactions and networks

STRING

4874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRKDC	XRCC6	P12956	999
PRKDC	XRCC5	P13010	999
PRKDC	XRCC4	Q13426	999
PRKDC	NHEJ1	Q9H9Q4	997
PRKDC	LIG4	P49917	989
PRKDC	DCLRE1C	Q96SD1	978
PRKDC	PARP1	P09874	976
PRKDC	WRN	Q14191	968
PRKDC	ATRIP	Q8WXE1	964
PRKDC	PAXX	Q9BUH6	949
PRKDC	HOXB7	P09629	938
PRKDC	EGFR	P00533	904
PRKDC	XRCC1	P18887	890
PRKDC	MDC1	Q14676	869
PRKDC	RPA2	P15927	864

IntAct

554 interactions, top by confidence:

A	B	Type	Score
rep	ISG15	psi-mi:“MI:0914”(association)	0.910
PRKDC	XRCC6	psi-mi:“MI:0915”(physical association)	0.900
PRKDC	XRCC5	psi-mi:“MI:0407”(direct interaction)	0.900
PRKDC	XRCC6	psi-mi:“MI:0217”(phosphorylation reaction)	0.900
PPP6C	ANKRD28	psi-mi:“MI:0914”(association)	0.870
RARA	NCOR1	psi-mi:“MI:0914”(association)	0.800
DCLRE1C	LIG4	psi-mi:“MI:0914”(association)	0.790
H3C1	HAT1	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
NHEJ1	XRCC5	psi-mi:“MI:0914”(association)	0.710
DCLRE1C	PRKDC	psi-mi:“MI:0915”(physical association)	0.700
XPA	HERC2	psi-mi:“MI:0914”(association)	0.680
LMNA	LMNB1	psi-mi:“MI:0914”(association)	0.680
XRCC5	HOXB7	psi-mi:“MI:0914”(association)	0.600
TELO2	MTOR	psi-mi:“MI:0914”(association)	0.600
TELO2	PRKDC	psi-mi:“MI:0914”(association)	0.600
PARP1	TOP2A	psi-mi:“MI:0914”(association)	0.600
NR1H4	PRKDC	psi-mi:“MI:0915”(physical association)	0.560
USF1	PARP1	psi-mi:“MI:0914”(association)	0.560
USF1	PARP1	psi-mi:“MI:0915”(physical association)	0.560
PAXX	XRCC5	psi-mi:“MI:0914”(association)	0.560
PA	IPO5	psi-mi:“MI:0914”(association)	0.550

BioGRID (1167): PRKDC (Affinity Capture-MS), PRKDC (Affinity Capture-Western), PRKDC (Reconstituted Complex), PRKDC (Biochemical Activity), TP53 (Biochemical Activity), PRKDC (Affinity Capture-MS), PRKDC (Affinity Capture-MS), PRKDC (Affinity Capture-MS), PRKDC (Biochemical Activity), PRKDC (Affinity Capture-MS), PRKDC (Affinity Capture-MS), PRKDC (Affinity Capture-MS), PRKDC (Affinity Capture-MS), PRKDC (Affinity Capture-MS), PRKDC (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4K859, A1Z7L1, A1ZBE8, A8WTE8, F4JC97, F4KBW6, F6S215, F6WXT2, O13665, O60287, O75691, P34343, P40090, P42173, P48322, P49815, P49816, P78527, P78847, Q03280, Q09716, Q21106, Q571H0, Q5SRE5, Q5WNI9, Q61037, Q6ZQH8, Q750S2, Q8BH53, Q8IQV9, Q8MYL1, Q8QGX4, Q8WN22, Q93903, Q95YE9, Q9C8Z4, Q9DEI1, Q9FIN7, Q9HDV6, Q9P7M6

Diamond homologs: O14356, O74630, P32600, P35169, P38110, P38111, P42345, P42346, P78527, Q02099, Q0DJS1, Q13315, Q2U639, Q4IB89, Q4WVM7, Q54ER4, Q59LR2, Q5ABX0, Q5BHE2, Q5EAK6, Q6BV76, Q6CAD2, Q6CP76, Q6CT34, Q6FRZ9, Q6PQD5, Q751J3, Q75DB8, Q7RZT9, Q86C65, Q8QGX4, Q8WN22, Q95Q95, Q9FR53, Q9JKK8, Q9JLN9, Q9M3G7, Q9VK45, Q9VXG8, Q9Y7K2

SIGNOR signaling

87 interactions.

A	Effect	B	Mechanism
PRKDC	up-regulates	IRF3	phosphorylation
PRKDC	up-regulates	RPA2	phosphorylation
PRKDC	unknown	RPA2	phosphorylation
PRKDC	down-regulates	LIG4	phosphorylation
PRKDC	up-regulates	CHEK2	phosphorylation
PRKDC	up-regulates	DCLRE1C	phosphorylation
ATR	up-regulates	PRKDC	phosphorylation
ATM	up-regulates	PRKDC	phosphorylation
PRKDC	up-regulates	PRKDC	phosphorylation
PRKDC	down-regulates	PRKDC	phosphorylation
PRKDC	up-regulates	PNKP	phosphorylation
PRKDC	unknown	NHEJ1	phosphorylation
XRCC6	up-regulates	PRKDC	relocalization
PRKDC	up-regulates	CASP2	phosphorylation
PRKDC	up-regulates	USF1	phosphorylation
PRKDC	up-regulates	HNRNPU	phosphorylation
PRKDC	up-regulates	TDP1	phosphorylation
PRKDC	up-regulates	H2AX	phosphorylation
8-(4-dibenzothiophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one	down-regulates	PRKDC	“chemical inhibition”
PRKDC	up-regulates	WRN	phosphorylation
PI-103	down-regulates	PRKDC	“chemical inhibition”
“PIK-75 Hydrochloride”	down-regulates	PRKDC	“chemical inhibition”
PP121	down-regulates	PRKDC	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 196 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Telomere Extension By Telomerase	5	17.6×	4e-03
Nuclear Envelope (NE) Reassembly	5	11.3×	6e-03
Nonhomologous End-Joining (NHEJ)	8	10.3×	9e-04
Meiotic synapsis	7	7.6×	6e-03
Interferon Signaling	7	6.5×	7e-03
Clathrin-mediated endocytosis	8	5.2×	9e-03
Diseases of signal transduction by growth factor receptors and second messengers	11	4.8×	4e-03
Cytokine Signaling in Immune system	12	3.8×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair via nonhomologous end joining	10	25.2×	8e-09
telomere maintenance	7	11.2×	1e-03
DNA damage response	15	4.8×	4e-04
negative regulation of apoptotic process	17	3.5×	2e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

4907 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	2580
Likely benign	2028
Benign	114

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
154322	NM_006904.7(PRKDC):c.9185T>G (p.Leu3062Arg)	Pathogenic
154323	NM_006904.7(PRKDC):c.10721C>T (p.Ala3574Val)	Pathogenic
688051	GRCh37/hg19 8q11.21(chr8:48730498-48829786)x1	Pathogenic
4813774	NM_006904.7(PRKDC):c.5589del (p.Phe1863fs)	Likely pathogenic

SpliceAI

11746 predictions. Top by Δscore:

Variant	Effect	Δscore
8:47774373:CATCA:C	acceptor_gain	1.0000
8:47774374:ATCA:A	acceptor_gain	1.0000
8:47774375:TCA:T	acceptor_gain	1.0000
8:47774376:CA:C	acceptor_gain	1.0000
8:47774376:CAC:C	acceptor_gain	1.0000
8:47774377:AC:A	acceptor_loss	1.0000
8:47774378:C:A	acceptor_loss	1.0000
8:47774378:C:CC	acceptor_gain	1.0000
8:47776982:TT:T	acceptor_gain	1.0000
8:47777680:ACCT:A	donor_loss	1.0000
8:47777681:CCT:C	donor_loss	1.0000
8:47777682:CTACT:C	donor_loss	1.0000
8:47777684:A:AC	donor_gain	1.0000
8:47777684:ACTT:A	donor_loss	1.0000
8:47777684:ACTTT:A	donor_gain	1.0000
8:47777685:C:CA	donor_gain	1.0000
8:47777685:CT:C	donor_gain	1.0000
8:47777685:CTT:C	donor_gain	1.0000
8:47777685:CTTT:C	donor_gain	1.0000
8:47777685:CTTTC:C	donor_gain	1.0000
8:47777688:T:A	donor_gain	1.0000
8:47777705:T:TA	donor_gain	1.0000
8:47777720:T:TA	donor_gain	1.0000
8:47777870:AGAAA:A	acceptor_gain	1.0000
8:47777871:GAAA:G	acceptor_gain	1.0000
8:47777872:AAA:A	acceptor_gain	1.0000
8:47777873:AA:A	acceptor_gain	1.0000
8:47777875:C:CC	acceptor_gain	1.0000
8:47779000:TTACT:T	donor_loss	1.0000
8:47779001:TA:T	donor_loss	1.0000

AlphaMissense

27291 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:47778490:T:A	D3941V	0.998
8:47782515:C:A	K3753N	0.998
8:47782515:C:G	K3753N	0.998
8:47855279:A:G	L2235P	0.998
8:47778489:G:C	D3941E	0.997
8:47778489:G:T	D3941E	0.997
8:47953665:C:A	G226W	0.997
8:47953665:C:G	G226R	0.997
8:47953665:C:T	G226R	0.997
8:47953670:A:G	L224P	0.997
8:47953817:A:G	L204P	0.997
8:47778490:T:C	D3941G	0.996
8:47778490:T:G	D3941A	0.996
8:47778531:G:C	N3927K	0.996
8:47778531:G:T	N3927K	0.996
8:47782486:C:G	R3763P	0.996
8:47852720:C:G	A2320P	0.996
8:47857179:A:G	W2196R	0.996
8:47857179:A:T	W2196R	0.996
8:47930687:A:G	L626P	0.996
8:47936468:A:G	L388P	0.996
8:47939579:G:T	A362D	0.996
8:47953893:C:G	G179R	0.996
8:47953893:C:T	G179R	0.996
8:47778486:A:C	F3942L	0.995
8:47778486:A:T	F3942L	0.995
8:47778488:A:G	F3942L	0.995
8:47782492:T:G	D3761A	0.995
8:47820794:A:C	S3087R	0.995
8:47820794:A:T	S3087R	0.995

dbSNP variants (sampled 300 via entrez): RS1000018604 (8:47951618 G>A), RS1000028807 (8:47904706 T>C), RS1000038694 (8:47872534 T>A,G), RS1000046009 (8:47829960 G>A), RS1000101325 (8:47859810 G>C), RS1000104955 (8:47788003 C>T), RS1000111866 (8:47872197 A>C), RS1000112407 (8:47912098 G>A), RS1000117768 (8:47798692 C>A,G,T), RS1000117895 (8:47792424 A>G), RS1000123101 (8:47904428 A>G), RS1000143123 (8:47944968 C>T), RS1000178558 (8:47848872 G>A), RS1000183043 (8:47913644 C>T), RS1000198303 (8:47841700 C>T)

Disease associations

OMIM: gene MIM:600899 | disease phenotypes: MIM:615966

GenCC curated gene-disease

Disease	Classification	Inheritance
severe combined immunodeficiency due to DNA-PKcs deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
severe combined immunodeficiency due to DNA-PKcs deficiency	Definitive	AR

Mondo (3): severe combined immunodeficiency due to DNA-PKcs deficiency (MONDO:0014423), breast cancer (MONDO:0007254), microcephaly (MONDO:0001149)

Orphanet (1): Severe combined immunodeficiency due to DNA-PKcs deficiency (Orphanet:317425)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000331	Short chin
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000490	Deeply set eye
HP:0000505	Visual impairment
HP:0001250	Seizure
HP:0001302	Pachygyria
HP:0001320	Cerebellar vermis hypoplasia
HP:0001511	Intrauterine growth retardation
HP:0002079	Hypoplasia of the corpus callosum
HP:0002783	Recurrent lower respiratory tract infections
HP:0003429	CNS hypomyelination
HP:0003593	Infantile onset
HP:0004430	Severe combined immunodeficiency
HP:0005403	Decreased total T cell count
HP:0009879	Simplified gyral pattern
HP:0010557	Overlapping fingers
HP:0010976	Decreased total B cell count
HP:0011107	Recurrent aphthous stomatitis
HP:0011220	Prominent forehead
HP:0012176	Abnormal natural killer cell morphology
HP:0012444	Brain atrophy

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST010988_295	Adult body size	5.000000e-08
GCST012490_495	Femur bone mineral density x serum urate levels interaction	2.000000e-08
GCST90002384_244	Hemoglobin	5.000000e-10
GCST90002390_604	Mean corpuscular hemoglobin	2.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004509	hemoglobin measurement
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3142 (SINGLE PROTEIN), CHEMBL4106136 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

23 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 110,870 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2216870	IDELALISIB	4	10,163
CHEMBL3643413	LENIOLISIB	4	341
CHEMBL422	TRIFLUOPERAZINE	4	20,044
CHEMBL1879463	DACTOLISIB	3	7,988
CHEMBL2017974	BUPARLISIB	3	6,568
CHEMBL265502	SURAMIN	3	36,848
CHEMBL4285417	CERALASERTIB	3	1,469
CHEMBL1236962	OMIPALISIB	2	3,989
CHEMBL1922094	APITOLISIB	2	3,070
CHEMBL2165191	AZD-6482	2	912
CHEMBL3120215	OSI-027	2	1,854
CHEMBL3360203	PILARALISIB	2	2,686
CHEMBL3586573	CC-115	2	1,240
CHEMBL3622533	FIMEPINOSTAT	2	2,487
CHEMBL3984425	EGANELISIB	2	1,200
CHEMBL3989870	BERZOSERTIB	2	1,265
CHEMBL4084907	BIMIRALISIB	2	1,625
CHEMBL521851	PICTILISIB	2	6,071
CHEMBL3112866	SAR-260301	1	728
CHEMBL3747513	CB-5083	1	322
CHEMBL4297629	NEDISERTIB	1
CHEMBL4439259	AZD-7648	1
CHEMBL4647810	ELIMUSERTIB	1

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Other PIKK family kinases

Most potent curated ligand interactions (16 total), top 16:

Ligand	Action	Affinity	Parameter
torin 2	Inhibition	9.3	pIC50
XRD-0394	Inhibition	9.2	pIC50
PIK-75	Inhibition	8.7	pIC50
compound 82 [PMID: 21332118]	Inhibition	8.52	pKi
peposertib	Inhibition	8.52	pIC50
KU-0060648	Inhibition	8.3	pIC50
NU-7441	Inhibition	7.85	pIC50
PI-103	Inhibition	7.64	pIC50
PP121	Inhibition	7.22	pIC50
BAY-8400	Inhibition	7.09	pIC50
AZD7648	Inhibition	7.04	pIC50
DNA-PK inhibitor III	Inhibition	6.92	pIC50
wortmannin	Inhibition	6.92	pKi
NU-7026	Inhibition	6.64	pIC50
DNA-PK inhibitor V	Inhibition	6.57	pIC50
lartesertib	Inhibition	6.22	pIC50

Binding affinities (BindingDB)

450 measured of 790 human assays (790 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
9-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one	IC50	0.07 nM	US-20250263753: BRIDGED CYCLE-BASED INHIBITORS OF DNA-DEPENDENT PROTEIN KINASE AND COMPOSITIONS AND APPLICATION IN GENE EDITING
2-[[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxymethyl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[8-[difluoro(phenyl)methoxy]-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
methyl 2-[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-2-(4-fluorophenyl)acetate	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl] 4-methylbenzenesulfonate	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-phenylphosphinic acid	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[7-methoxy-3-methyl-8-[[3-(morpholin-4-ylmethyl)phenyl]methoxy]pyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[7-methoxy-3-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-ylmethoxy)pyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[8-[[3-(aminomethyl)phenyl]methoxy]-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxymethyl]pyridine-2-carbonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[8-[[3-(dimethylamino)phenyl]methoxy]-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-[7-methoxy-3-methyl-8-[[3-(2-methyl-1,3-thiazol-4-yl)phenyl]methoxy]pyrazolo[3,4-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
2-[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-N-[2-(4-ethylpiperazin-1-yl)ethyl]-2-(4-fluorophenyl)acetamide	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
2-[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-N-[2-(dimethylamino)ethyl]-2-(4-fluorophenyl)acetamide	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
N-(cyanomethoxy)-2-[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-2-(4-fluorophenyl)acetamide	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
2-[1-(4-cyanophenyl)-7-methoxy-3-methylpyrazolo[3,4-c]quinolin-8-yl]oxy-2-(4-fluorophenyl)-N-(2-sulfamoylethyl)acetamide	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-(3-ethyl-7,8-dimethoxypyrazolo[3,4-c]quinolin-1-yl)-3-fluorobenzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-(7,8-dimethoxy-3-propylpyrazolo[3,4-c]quinolin-1-yl)benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-(7,8-dimethoxy-3-propan-2-ylpyrazolo[3,4-c]quinolin-1-yl)benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-(3-cyclopropyl-7,8-dimethoxypyrazolo[3,4-c]quinolin-1-yl)benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
4-(7,8-dimethoxy-3-prop-2-enylpyrazolo[3,4-c]quinolin-1-yl)benzonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
1-(4-cyanophenyl)-7,8-dimethoxypyrazolo[3,4-c]quinoline-3-carbonitrile	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
2-[1-(4-cyanophenyl)-7,8-dimethoxypyrazolo[3,4-c]quinolin-3-yl]acetic acid	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
2-[1-(4-cyanophenyl)-7,8-dimethoxypyrazolo[3,4-c]quinolin-3-yl]acetamide	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
1-[4-(4-ethylpiperazin-1-yl)phenyl]-7,8-dimethoxy-3-methylpyrazolo[3,4-c]quinoline	IC50	0.3 nM	US-8802712: Pyrazoloquinolines
2-[1-(4-cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxoimidazo[4,5-c]quinolin-8-yl]oxy-2-(4-fluorophenyl)-N-(2-methoxyethyl)acetamide	IC50	0.3 nM	US-9000153: Imidazo[4,5-c]quinolines as DNA-PK inhibitors
3-fluoro-4-[7-methoxy-3-methyl-8-[(3-morpholin-4-ylsulfonylthiophen-2-yl)methoxy]-2-oxoimidazo[4,5-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-9000153: Imidazo[4,5-c]quinolines as DNA-PK inhibitors
4-[8-(2-amino-1-thiophen-2-ylethoxy)-7-methoxy-3-methyl-2-oxoimidazo[4,5-c]quinolin-1-yl]-3-fluorobenzonitrile	IC50	0.3 nM	US-9000153: Imidazo[4,5-c]quinolines as DNA-PK inhibitors
3-fluoro-4-[7-methoxy-3-methyl-8-(2-methylpyrazol-3-yl)-2-oxoimidazo[4,5-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-9000153: Imidazo[4,5-c]quinolines as DNA-PK inhibitors
3-fluoro-4-[7-methoxy-3-methyl-8-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-2-oxoimidazo[4,5-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-9000153: Imidazo[4,5-c]quinolines as DNA-PK inhibitors
3-fluoro-4-[7-methoxy-3-methyl-2-oxo-8-(2-thiophen-3-ylethyl)imidazo[4,5-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-9000153: Imidazo[4,5-c]quinolines as DNA-PK inhibitors
3-fluoro-4-[7-methoxy-3-methyl-2-oxo-8-[(E)-2-phenylethenyl]imidazo[4,5-c]quinolin-1-yl]benzonitrile	IC50	0.3 nM	US-9000153: Imidazo[4,5-c]quinolines as DNA-PK inhibitors
9-(4-hydroxybicyclo[2.2.2]octan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one	IC50	0.71 nM	US-20250263753: BRIDGED CYCLE-BASED INHIBITORS OF DNA-DEPENDENT PROTEIN KINASE AND COMPOSITIONS AND APPLICATION IN GENE EDITING
4-[8-[2-amino-1-(4-fluorophenyl)ethoxy]-7-methoxy-3-methyl-2-oxoimidazo[4,5-c]quinolin-1-yl]-3-fluorobenzonitrile	IC50	0.75 nM	US-9000153: Imidazo[4,5-c]quinolines as DNA-PK inhibitors
N-(4-((7-morpholinoimidazo[1,2-c]pyrimidin-5-yl)oxy)cyclohexyl)pyrazin-2-amine	IC50	0.75 nM	US-20250326754: DNA-PK Inhibitor Compounds and Uses Thereof
N-(4-((7-morpholinoimidazo[1,2-c]pyrimidin-5-yl)oxy)cyclohexyl)pyridin-2-amine	IC50	0.75 nM	US-20250326754: DNA-PK Inhibitor Compounds and Uses Thereof
N-(4-((7-morpholinoimidazo[1,2-c]pyrimidin-5-yl)oxy)cyclohexyl)pyrazolo[1,5-a]pyrimidin-5-amine	IC50	0.75 nM	US-20250326754: DNA-PK Inhibitor Compounds and Uses Thereof
N-(4-((7-morpholino-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine	IC50	0.75 nM	US-20250326754: DNA-PK Inhibitor Compounds and Uses Thereof
N,N-dimethyl-2-((2-((4-((7-morpholino-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)oxy)cyclohexyl)amino)pyrimidin-5-yl)oxy)acetamide	IC50	0.75 nM	US-20250326754: DNA-PK Inhibitor Compounds and Uses Thereof
N,N-dimethyl-2-(2-((4-((7-morpholino-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)oxy)cyclohexyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetamide	IC50	0.75 nM	US-20250326754: DNA-PK Inhibitor Compounds and Uses Thereof
N-(4-((7-morpholino-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)oxy)cyclohexyl)pyrazin-2-amine	IC50	0.75 nM	US-20250326754: DNA-PK Inhibitor Compounds and Uses Thereof
5-fluoro-N-(4-((7-morpholino-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine	IC50	0.75 nM	US-20250326754: DNA-PK Inhibitor Compounds and Uses Thereof
4-methyl-N-(4-((7-morpholino-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine	IC50	0.75 nM	US-20250326754: DNA-PK Inhibitor Compounds and Uses Thereof
1-methyl-6-morpholin-4-yl-8-(4-pyrimidin-2-yloxycyclohexyl)oxyquinoxalin-2-one	KI	2 nM	US-12269804: Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency
1-methyl-8-[4-[(2-methyl-6,7-dihydrofuro[3,2-d]pyrimidin-4-yl)amino]cyclohexyl]oxy-6-morpholin-4-ylquinoxalin-2-one	KI	2 nM	US-12269804: Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency
1-methyl-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-8-(4-pyrimidin-2-yloxycyclohexyl)oxyquinoxalin-2-one	KI	2 nM	US-12269804: Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency
1-methyl-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-(4-pyrimidin-2-yloxycyclohexyl)oxyquinoxalin-2-one	KI	2 nM	US-12269804: Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency
1-methyl-8-[4-(5-methylpyrimidin-2-yl)oxycyclohexyl]oxy-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)quinoxalin-2-one	KI	2 nM	US-12269804: Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency
1-methyl-6-morpholin-4-yl-8-[4-(pyrimidin-2-ylamino)cyclohexyl]oxyquinoxalin-2-one	KI	3 nM	US-12269804: Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency
8-[4-(5-methoxypyrimidin-2-yl)oxycyclohexyl]oxy-1-methyl-6-morpholin-4-ylquinoxalin-2-one	KI	3 nM	US-12269804: Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency

ChEMBL bioactivities

2090 potent at pChembl≥5 of 2153 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.10	IC50	0.07943	nM	CHEMBL4447991
10.00	IC50	0.1	nM	CHEMBL5566630
10.00	IC50	0.1	nM	CHEMBL5563688
9.96	IC50	0.11	nM	CHEMBL5570653
9.92	IC50	0.12	nM	CHEMBL5180090
9.89	IC50	0.13	nM	CHEMBL5194436
9.80	IC50	0.1585	nM	CHEMBL4560221
9.80	IC50	0.158	nM	CHEMBL6065576
9.80	IC50	0.158	nM	CHEMBL5890243
9.80	IC50	0.158	nM	CHEMBL4560221
9.70	IC50	0.1995	nM	CHEMBL4450232
9.70	IC50	0.2	nM	CHEMBL5591635
9.70	IC50	0.2	nM	CHEMBL5889927
9.60	IC50	0.2512	nM	CHEMBL4553941
9.60	IC50	0.251	nM	CHEMBL5980589
9.55	IC50	0.28	nM	OMIPALISIB
9.52	IC50	0.3	nM	CHEMBL3646708
9.52	IC50	0.3	nM	CHEMBL3646711
9.52	IC50	0.3	nM	CHEMBL3646712
9.52	IC50	0.3	nM	CHEMBL3646718
9.52	IC50	0.3	nM	CHEMBL3646719
9.52	IC50	0.3	nM	CHEMBL3646722
9.52	IC50	0.3	nM	CHEMBL3646724
9.52	IC50	0.3	nM	CHEMBL3646726
9.52	IC50	0.3	nM	CHEMBL3646732
9.52	IC50	0.3	nM	CHEMBL3646735
9.52	IC50	0.3	nM	CHEMBL3639456
9.52	IC50	0.3	nM	CHEMBL3646741
9.52	IC50	0.3	nM	CHEMBL3646742
9.52	IC50	0.3	nM	CHEMBL3646744
9.52	IC50	0.3	nM	CHEMBL3646745
9.52	IC50	0.3	nM	CHEMBL3646750
9.52	IC50	0.3	nM	CHEMBL3646752
9.52	IC50	0.3	nM	CHEMBL3646753
9.52	IC50	0.3	nM	CHEMBL3646755
9.52	IC50	0.3	nM	CHEMBL3646756
9.52	IC50	0.3	nM	CHEMBL3646758
9.52	IC50	0.3	nM	CHEMBL3646760
9.52	IC50	0.3	nM	CHEMBL3646761
9.52	IC50	0.3	nM	CHEMBL3646768
9.52	IC50	0.3	nM	CHEMBL3667683
9.52	IC50	0.3	nM	CHEMBL3667686
9.52	IC50	0.3	nM	CHEMBL3672673
9.52	IC50	0.3	nM	CHEMBL3672679
9.52	IC50	0.3	nM	CHEMBL3672681
9.52	IC50	0.3	nM	CHEMBL3672683
9.52	IC50	0.3	nM	CHEMBL3672684
9.50	IC50	0.3162	nM	CHEMBL4555040
9.50	IC50	0.3162	nM	CHEMBL4581254
9.50	IC50	0.316	nM	CHEMBL4581254

PubChem BioAssay actives

1134 with measured affinity, of 2120 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
9-(4-hydroxycyclohexyl)-7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0001	uM
7-methyl-2-[(7-methylquinolin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
7-methyl-2-[(7-methylquinoxalin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
7-methyl-2-[(7-methylcinnolin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
7-methyl-2-[(7-methylquinazolin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
7-methyl-2-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0001	uM
7-methyl-2-[(4-methyl-6-thiophen-2-yl-3-pyridinyl)amino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0001	uM
N-(6-methylquinolin-7-yl)-5-(oxan-4-yl)-4H-[1,2,4]triazolo[4,3-f]pteridin-7-amine	2104207: Inhibition of human full-length DNA-PK using EPPLSQEAFADLWKK as substrate incubated for 60 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0001	uM
9-cyclohexyl-7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0002	uM
9-(4,4-difluorocyclohexyl)-7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0002	uM
5-[4-methyl-5-[[7-methyl-9-(oxan-4-yl)-8-oxopurin-2-yl]amino]-2-pyridinyl]furan-2-carbaldehyde	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0002	uM
9-(4-hydroxy-4-methylcyclohexyl)-7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0003	uM
9-(4-hydroxycyclohexyl)-2-(4-methoxy-2-methylanilino)-7-methylpurin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0003	uM
9-(4-hydroxycyclohexyl)-7-methyl-2-[(7-methylimidazo[1,2-a]pyridin-6-yl)amino]purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0003	uM
N-(6-methylquinolin-7-yl)-5-(oxan-4-yl)-6H-imidazo[1,2-f]pteridin-3-amine	2104207: Inhibition of human full-length DNA-PK using EPPLSQEAFADLWKK as substrate incubated for 60 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0003	uM
2,4-difluoro-N-[2-methoxy-5-(4-pyridazin-4-ylquinolin-6-yl)-3-pyridinyl]benzenesulfonamide	2154071: Inhibition of DNA-PK (unknown origin)	ic50	0.0003	uM
7-methyl-2-[(7-methylimidazo[1,2-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0004	uM
7-methyl-2-[(7-methylquinolin-6-yl)amino]-9-[(3S)-1-(oxetan-3-yl)pyrrolidin-3-yl]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0004	uM
7-methyl-2-[2-methyl-4-(1H-1,2,4-triazol-5-yl)anilino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0004	uM
7-methyl-2-[[4-methyl-6-(1H-pyrazol-4-yl)-3-pyridinyl]amino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0004	uM
2-[[6-[1-(difluoromethyl)pyrazol-4-yl]-4-methyl-3-pyridinyl]amino]-7-methyl-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0004	uM
(S)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol	2066816: Inhibition of human DNA-PK using EPPLSQEAFADLWK as substrate in presence of ATP by kinase hotspot assay	ic50	0.0004	uM
6-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-3H-quinazolin-4-one	507077: Inhibition of DNA-PK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0005	uM
9-[(3R,4R)-4-fluoropyrrolidin-3-yl]-7-methyl-2-[(7-methylquinolin-6-yl)amino]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0005	uM
9-(6-amino-3-pyridinyl)-1-[3-(trifluoromethyl)phenyl]benzo[h][1,6]naphthyridin-2-one	591849: Inhibition of DNA-PK	ic50	0.0005	uM
8-dibenzothiophen-4-yl-2-morpholin-4-ylchromen-4-one	257403: Inhibitory activity against DNA-dependent protein kinase receptor	ki	0.0006	uM
7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purin-8-one	1604742: Inhibition of human HeLa cell-derived full length DNA-PK catalytic subunit using fluorescein-EPPLSQEAFADLWKK as substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins TR-FRET assay	ic50	0.0006	uM
9-[(3R,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-7-methyl-2-[(7-methylquinolin-6-yl)amino]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0006	uM
1-methyl-N-(6-methylquinolin-7-yl)-5-(oxan-4-yl)-4H-[1,2,4]triazolo[4,3-f]pteridin-7-amine	2104207: Inhibition of human full-length DNA-PK using EPPLSQEAFADLWKK as substrate incubated for 60 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0006	uM
7-methyl-9-(1-methylpiperidin-4-yl)-2-[(7-methylquinoxalin-6-yl)amino]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0007	uM
7-methyl-2-[(7-methylquinolin-6-yl)amino]-9-piperidin-4-ylpurin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0007	uM
2-[[6-(furan-2-yl)-4-methyl-3-pyridinyl]amino]-7-methyl-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0007	uM
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-1-yl)phenyl]propanenitrile	2066816: Inhibition of human DNA-PK using EPPLSQEAFADLWK as substrate in presence of ATP by kinase hotspot assay	ic50	0.0008	uM
5-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-(oxan-4-yl)-7H-pteridin-6-one	1867755: Inhibition of human native full length DNA-PK by ADP-Glo assay	ic50	0.0008	uM
7-methyl-2-[(4-methyl-6-thiophen-3-yl-3-pyridinyl)amino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0008	uM
2-[[6-(furan-3-yl)-4-methyl-3-pyridinyl]amino]-7-methyl-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0008	uM
9-[(3S)-1-(2-hydroxyethyl)pyrrolidin-3-yl]-7-methyl-2-[(7-methylquinolin-6-yl)amino]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0008	uM
N-[5-(7’-fluoro-3’-methyl-2’-oxospiro[cyclobutane-1,1’-pyrrolo[2,3-c]quinoline]-8’-yl)-2-[2-(propan-2-ylamino)ethoxy]-3-pyridinyl]methanesulfonamide	2066601: Inhibition of DNA-PK in human HCT-116 cells measured after 1 hr by Bradford assay	ic50	0.0009	uM
7-methyl-2-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]-9-piperidin-4-ylpurin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0009	uM
N-[2-[3-(dimethylamino)propoxy]-5-(3’-methyl-2’-oxospiro[cyclobutane-1,1’-pyrrolo[2,3-c]quinoline]-8’-yl)-3-pyridinyl]-1,1,1-trifluoromethanesulfonamide	1872253: Inhibition of full-length human DNA-PK expressed in baculovirus expression system using p53 as substrate incubated for 1 hr in presence of ATP by ELISA	ic50	0.0010	uM
N-[2-[3-(dimethylamino)propoxy]-5-(3’-methyl-2’-oxospiro[cyclobutane-1,1’-pyrrolo[2,3-c]quinoline]-8’-yl)-3-pyridinyl]-2-ethyl-1,3-thiazole-5-sulfonamide	1872253: Inhibition of full-length human DNA-PK expressed in baculovirus expression system using p53 as substrate incubated for 1 hr in presence of ATP by ELISA	ic50	0.0010	uM
7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)purin-8-one	1872240: Inhibition of human DNA-PK using p53 as substrate incubated for 30 mins in presence of by HTRF assay	ic50	0.0010	uM
1,1,5’-trimethyl-2’-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]spiro[cyclohexane-4,7’-pyrrolo[3,2-d]pyrimidine]-6’-one	1872240: Inhibition of human DNA-PK using p53 as substrate incubated for 30 mins in presence of by HTRF assay	ic50	0.0010	uM
2-(5-acetyl-2,3-dihydroindol-1-yl)-7-methyl-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
2-[[6-(3,4-dimethoxyphenyl)-4-methyl-3-pyridinyl]amino]-7-methyl-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
7-methyl-2-[[5-methyl-2-(1-methylpyrazol-4-yl)-4-pyridinyl]amino]-9-(oxan-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
9-[(3R,5S)-3,5-dimethyl-1-adamantyl]-7-methyl-2-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
9-(1-acetylpiperidin-4-yl)-7-methyl-2-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
7-methyl-2-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]-9-(1-methylsulfonylpiperidin-4-yl)purin-8-one	2092847: Inhibition of human DNA-PK incubated for 30 mins in presence of Mg/ATP by HTRF method	ic50	0.0010	uM
7-methyl-9-[(3S)-1-methylpyrrolidin-3-yl]-2-[(7-methylquinolin-6-yl)amino]purin-8-one	1886987: Inhibition of DNA-PK (unknown origin) using EPPLSQEAFADLWKK peptide as substrate preincubated with compound for 30 mins followed by substrate addition and further incubated for 40 mins in presence of ATP by TR-FRET assay	ic50	0.0014	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects binding, decreases reaction, decreases phosphorylation, increases reaction, decreases activity (+3 more)	5
Benzo(a)pyrene	decreases expression, decreases methylation, affects methylation	5
Estradiol	affects cotreatment, increases expression, decreases expression	5
Arsenic	increases response to substance, affects cotreatment, increases abundance, decreases expression, increases expression (+1 more)	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Cisplatin	decreases response to substance, increases expression, affects cotreatment, increases response to substance	3
Doxorubicin	increases phosphorylation, increases reaction, decreases expression, decreases reaction, affects reaction (+1 more)	3
arsenite	affects binding, decreases reaction, increases activity, increases phosphorylation, increases reaction (+2 more)	2
cobaltous chloride	decreases expression	2
2-(morpholin-4-yl)benzo(h)chromen-4-one	decreases activity, decreases phosphorylation, increases reaction	2
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression, increases expression, affects response to substance	2
IC486241	decreases reaction, increases phosphorylation, increases reaction	2
Bortezomib	decreases reaction, increases cleavage, decreases expression, affects reaction, increases activity	2
Irinotecan	decreases reaction, increases phosphorylation	2
Benzene	affects expression, increases expression	2
Caffeine	affects phosphorylation, increases activity, increases phosphorylation, increases reaction	2
Curcumin	decreases expression, decreases reaction	2
Fluorouracil	decreases expression, affects cotreatment, increases response to substance, affects reaction	2
Nickel	increases expression	2
Tretinoin	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Phenol	increases expression, affects localization	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
lasiocarpine	increases expression	1
myristicin	decreases expression	1
triphenyl phosphate	affects expression	1

ChEMBL screening assays

363 unique, capped per target: 363 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1054863	Binding	Inhibition of DNA-PK at 10 uM by HotSpot assay relative to control	Design, synthesis and biological evaluation of new potent and highly selective ROS1-tyrosine kinase inhibitor. — Bioorg Med Chem Lett

Cellosaurus cell lines

13 cell lines: 12 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0400	M059J	Cancer cell line	Male
CVCL_1R01	HCT116-DNAPKcs(+/-)	Cancer cell line	Male
CVCL_B9QF	Abcam A-549 PRKDC KO	Cancer cell line	Male
CVCL_D9PU	Ubigene HEK293 PRKDC KO	Transformed cell line	Female
CVCL_DX08	HAP1 PRKDC (-) PAXX (-)	Cancer cell line	Male
CVCL_DX10	HAP1 PRKDC (-) XRCC4 (-)	Cancer cell line	Male
CVCL_F1MC	HyCyte A-549 KO-hPRKDC	Cancer cell line	Male
CVCL_HD89	HCT 116 PRKDC(+/-)	Cancer cell line	Male
CVCL_HD90	HCT 116 PRKDC(-/-)	Cancer cell line	Male
CVCL_HE07	NALM-6 PRKDC(+/-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	PHASE4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	PHASE4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	PHASE4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	PHASE4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	PHASE4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	PHASE4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	PHASE4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	PHASE4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	PHASE4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	PHASE4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer
NCT00754767	PHASE4	TERMINATED	L-Carnitine L-Tartrate in Preventing Peripheral Neuropathy Caused By Chemotherapy in Women With Metastatic Breast Cancer