DNA-PKcs

DNA-PKcs is the catalytic subunit of a nuclear DNA-dependent serine/threonine protein kinase called DNA-PK. The second component is the autoimmune antigen Ku. On its own, DNA-PKcs is inactive and relies on Ku to direct it to DNA ends and trigger its kinase activity.{{cite web | title = Entrez Gene: PRKDC protein kinase, DNA-activated, catalytic polypeptide| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5591}} DNA-PKcs is required for the non-homologous end joining (NHEJ) pathway of DNA repair, which rejoins double-strand breaks. It is also required for V(D)J recombination, a process that utilizes NHEJ to promote immune system diversity.

Many proteins have been identified as substrates for the kinase activity of DNA-PK. Autophosphorylation of DNA-PKcs appears to play a key role in NHEJ and is thought to induce a conformational change that allows end processing enzymes to access the ends of the double-strand break.{{Cite book |vauthors=Meek K, Dang V, Lees-Miller SP |title=Chapter 2 DNA-PK |volume=99 |pages=33–58 |year=2008 |pmid=19117531 |doi=10.1016/S0065-2776(08)00602-0 |series=Advances in Immunology |isbn=9780123743251 }} DNA-PK also cooperates with ATR and ATM to phosphorylate proteins involved in the DNA damage checkpoint.

DNA-PKcs knockout mice have severe combined immunodeficiency due to their V(D)J recombination defect. Natural analogs of this knockout happen in mice, horses and dogs, also causing SCID.{{cite journal | vauthors = Meek K, Jutkowitz A, Allen L, Glover J, Convery E, Massa A, Mullaney T, Stanley B, Rosenstein D, Bailey SM, Johnson C, Georges G | title = SCID dogs: similar transplant potential but distinct intra-uterine growth defects and premature replicative senescence compared with SCID mice | journal = Journal of Immunology | volume = 183 | issue = 4 | pages = 2529–36 | date = August 2009 | pmid = 19635917 | doi = 10.4049/jimmunol.0801406 | pmc = 4047667 }} Human SCID usually have other causes, but two cases related to mutations in this gene are also known.{{cite journal | vauthors = Anne Esguerra Z, Watanabe G, Okitsu CY, Hsieh CL, Lieber MR | title = DNA-PKcs chemical inhibition versus genetic mutation: Impact on the junctional repair steps of V(D)J recombination | journal = Molecular Immunology | volume = 120 | pages = 93–100 | date = April 2020 | pmid = 32113132 | pmc = 7184946 | doi = 10.1016/j.molimm.2020.01.018 }}

DNA-PKcs activates p53 to regulate apoptosis.{{cite journal |vauthors=Wang S, Guo M, Ouyang H, Li X, Cordon-Cardo C, Kurimasa A, Chen DJ, Fuks Z, Ling CC, Li GC |title=The catalytic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest |journal=Proc Natl Acad Sci U S A |volume=97 |issue=4 |pages=1584–8 |date=February 2000 |pmid=10677503 |pmc=26478 |doi=10.1073/pnas.97.4.1584 }} In response to ionizing radiation, DNA-PKcs can serve as an upstream effector for p53 protein activation, thus linking DNA damage to apoptosis. Both Repair of DNA damages and apoptosis are catalytic activities required for maintaining integrity of the human genome. Cells that have insufficient DNA repair capability tend to accumulate DNA damages, and when such cells are additionally defective in apoptosis they tend to survive even though excessive DNA damages are present.{{cite journal |vauthors=Bernstein C, Bernstein H, Payne CM, Garewal H |title=DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis |journal=Mutat Res |volume=511 |issue=2 |pages=145–78 |date=June 2002 |pmid=12052432 |doi=10.1016/s1383-5742(02)00009-1 }} The replication of DNA in such deficient cells can generate mutations and such mutations may cause cancer. Thus DNA-PKcs appears to have two functions related to the prevention of cancer, where the first function is to participate in the repair of DNA double-strand breaks by the NHEJ repair pathway and the second function is to induce apoptosis if the level of such DNA breaks exceed the cell’s repair capability

DNA damage appears to be the primary underlying cause of cancer,{{cite journal | vauthors = Kastan MB | title = DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture | journal = Molecular Cancer Research | volume = 6 | issue = 4 | pages = 517–524 | date = April 2008 | pmid = 18403632 | doi = 10.1158/1541-7786.MCR-08-0020 | doi-access = free }} and deficiencies in DNA repair genes likely underlie many forms of cancer.{{cite journal | vauthors = Harper JW, Elledge SJ | title = The DNA damage response: ten years after | journal = Molecular Cell | volume = 28 | issue = 5 | pages = 739–745 | date = December 2007 | pmid = 18082599 | doi = 10.1016/j.molcel.2007.11.015 | doi-access = free }}{{cite journal | vauthors = Dietlein F, Reinhardt HC | title = Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy | journal = Clinical Cancer Research | volume = 20 | issue = 23 | pages = 5882–7 | date = December 2014 | pmid = 25451105 | doi = 10.1158/1078-0432.CCR-14-1165 | doi-access = }} If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutations due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair.{{cite journal | vauthors = O'Hagan HM, Mohammad HP, Baylin SB | title = Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island | journal = PLOS Genetics | volume = 4 | issue = 8 | pages = e1000155 | date = August 2008 | pmid = 18704159 | pmc = 2491723 | doi = 10.1371/journal.pgen.1000155 | doi-access = free }}{{cite journal | vauthors = Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV | title = DNA damage, homology-directed repair, and DNA methylation | journal = PLOS Genetics | volume = 3 | issue = 7 | pages = e110 | date = July 2007 | pmid = 17616978 | pmc = 1913100 | doi = 10.1371/journal.pgen.0030110 | doi-access = free }} Such mutations and epigenetic alterations may give rise to cancer.

PRKDC (DNA-PKcs) mutations were found in 3 out of 10 of endometriosis-associated ovarian cancers, as well as in the field defects from which they arose.{{cite journal | vauthors = Er TK, Su YF, Wu CC, Chen CC, Wang J, Hsieh TH, Herreros-Villanueva M, Chen WT, Chen YT, Liu TC, Chen HS, Tsai EM | title = Targeted next-generation sequencing for molecular diagnosis of endometriosis-associated ovarian cancer | journal = Journal of Molecular Medicine | volume = 94 | issue = 7 | pages = 835–847 | date = July 2016 | pmid = 26920370 | doi = 10.1007/s00109-016-1395-2 | s2cid = 16399834 }} They were also found in 10% of breast and pancreatic cancers.{{cite journal | vauthors = Wang X, Szabo C, Qian C, Amadio PG, Thibodeau SN, Cerhan JR, Petersen GM, Liu W, Couch FJ | title = Mutational analysis of thirty-two double-strand DNA break repair genes in breast and pancreatic cancers | journal = Cancer Research | volume = 68 | issue = 4 | pages = 971–5 | date = February 2008 | pmid = 18281469 | doi = 10.1158/0008-5472.CAN-07-6272 | doi-access = free }}

Reductions in expression of DNA repair genes (usually caused by epigenetic alterations) are very common in cancers, and are ordinarily even more frequent than mutational defects in DNA repair genes in cancers.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} DNA-PKcs expression was reduced by 23% to 57% in six cancers as indicated in the table.

It is not clear what causes reduced expression of DNA-PKcs in cancers. MicroRNA-101 targets DNA-PKcs via binding to the 3'- UTR of DNA-PKcs mRNA and efficiently reduces protein levels of DNA-PKcs.{{cite journal | vauthors = Yan D, Ng WL, Zhang X, Wang P, Zhang Z, Mo YY, Mao H, Hao C, Olson JJ, Curran WJ, Wang Y | title = Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation | journal = PLOS ONE | volume = 5 | issue = 7 | pages = e11397 | date = July 2010 | pmid = 20617180 | pmc = 2895662 | doi = 10.1371/journal.pone.0011397 | doi-access = free | bibcode = 2010PLoSO...511397Y }} But miR-101 is more often decreased in cancers, rather than increased.{{cite journal | vauthors = Li M, Tian L, Ren H, Chen X, Wang Y, Ge J, Wu S, Sun Y, Liu M, Xiao H | title = MicroRNA-101 is a potential prognostic indicator of laryngeal squamous cell carcinoma and modulates CDK8 | journal = Journal of Translational Medicine | volume = 13 | pages = 271 | date = August 2015 | pmid = 26286725 | pmc = 4545549 | doi = 10.1186/s12967-015-0626-6 | doi-access = free }}{{cite journal | vauthors = Liu Z, Wang J, Mao Y, Zou B, Fan X | title = MicroRNA-101 suppresses migration and invasion via targeting vascular endothelial growth factor-C in hepatocellular carcinoma cells | journal = Oncology Letters | volume = 11 | issue = 1 | pages = 433–8 | date = January 2016 | pmid = 26870229 | pmc = 4727073 | doi = 10.3892/ol.2015.3832 }}

HMGA2 protein could also have an effect on DNA-PKcs. HMGA2 delays the release of DNA-PKcs from sites of double-strand breaks, interfering with DNA repair by non-homologous end joining and causing chromosomal aberrations.{{cite journal | vauthors = Li AY, Boo LM, Wang SY, Lin HH, Wang CC, Yen Y, Chen BP, Chen DJ, Ann DK | title = Suppression of nonhomologous end joining repair by overexpression of HMGA2 | journal = Cancer Research | volume = 69 | issue = 14 | pages = 5699–5706 | date = July 2009 | pmid = 19549901 | pmc = 2737594 | doi = 10.1158/0008-5472.CAN-08-4833 }} The let-7a microRNA normally represses the HMGA2 gene.{{cite journal | vauthors = Motoyama K, Inoue H, Nakamura Y, Uetake H, Sugihara K, Mori M | title = Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family | journal = Clinical Cancer Research | volume = 14 | issue = 8 | pages = 2334–40 | date = April 2008 | pmid = 18413822 | doi = 10.1158/1078-0432.CCR-07-4667 | doi-access = free }}{{cite journal | vauthors = Wu A, Wu K, Li J, Mo Y, Lin Y, Wang Y, Shen X, Li S, Li L, Yang Z | title = Let-7a inhibits migration, invasion and epithelial-mesenchymal transition by targeting HMGA2 in nasopharyngeal carcinoma | journal = Journal of Translational Medicine | volume = 13 | pages = 105 | date = March 2015 | pmid = 25884389 | pmc = 4391148 | doi = 10.1186/s12967-015-0462-8 | doi-access = free }} In normal adult tissues, almost no HMGA2 protein is present. In many cancers, let-7 microRNA is repressed. As an example, in breast cancers the promoter region controlling let-7a-3/let-7b microRNA is frequently repressed by hypermethylation.{{cite journal | vauthors = Vrba L, Muñoz-Rodríguez JL, Stampfer MR, Futscher BW | title = miRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer | journal = PLOS ONE | volume = 8 | issue = 1 | pages = e54398 | year = 2013 | pmid = 23342147 | pmc = 3547033 | doi = 10.1371/journal.pone.0054398 | doi-access = free | bibcode = 2013PLoSO...854398V }} Epigenetic reduction or absence of let-7a microRNA allows high expression of the HMGA2 protein and this would lead to defective expression of DNA-PKcs.

DNA-PKcs can be up-regulated by stressful conditions such as in Helicobacter pylori-associated gastritis.{{cite journal | vauthors = Lee HS, Choe G, Park KU, Park DJ, Yang HK, Lee BL, Kim WH | title = Altered expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) during gastric carcinogenesis and its clinical implications on gastric cancer | journal = International Journal of Oncology | volume = 31 | issue = 4 | pages = 859–866 | date = October 2007 | pmid = 17786318 | doi = 10.3892/ijo.31.4.859 | doi-access = free }} After ionizing radiation DNA-PKcs was increased in the surviving cells of oral squamous cell carcinoma tissues.{{cite journal | vauthors = Shintani S, Mihara M, Li C, Nakahara Y, Hino S, Nakashiro K, Hamakawa H | title = Up-regulation of DNA-dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma | journal = Cancer Science | volume = 94 | issue = 10 | pages = 894–900 | date = October 2003 | pmid = 14556663 | doi = 10.1111/j.1349-7006.2003.tb01372.x | s2cid = 2126685 | pmc = 11160163 }}

The ATM protein is important in homologous recombinational repair (HRR) of DNA double strand breaks. When cancer cells are deficient in ATM the cells are "addicted" to DNA-PKcs, important in the alternative DNA repair pathway for double-strand breaks, non-homologous end joining (NHEJ).{{cite journal | vauthors = Riabinska A, Daheim M, Herter-Sprie GS, Winkler J, Fritz C, Hallek M, Thomas RK, Kreuzer KA, Frenzel LP, Monfared P, Martins-Boucas J, Chen S, Reinhardt HC | title = Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors | journal = Science Translational Medicine | volume = 5 | issue = 189 | pages = 189ra78 | date = June 2013 | pmid = 23761041 | doi = 10.1126/scitranslmed.3005814 | s2cid = 206681916 }} That is, in ATM-mutant cells, an inhibitor of DNA-PKcs causes high levels of apoptotic cell death. In ATM mutant cells, additional loss of DNA-PKcs leaves the cells without either major pathway (HRR and NHEJ) for repair of DNA double-strand breaks.

Elevated DNA-PKcs expression is found in a large fraction (40% to 90%) of some cancers (the remaining fraction of cancers often has reduced or absent expression of DNA-PKcs). The elevation of DNA-PKcs is thought to reflect the induction of a compensatory DNA repair capability, due to the genome instability in these cancers.{{cite journal | vauthors = Hsu FM, Zhang S, Chen BP | title = Role of DNA-dependent protein kinase catalytic subunit in cancer development and treatment | journal = Translational Cancer Research | volume = 1 | issue = 1 | pages = 22–34 | date = June 2012 | pmid = 22943041 | pmc = 3431019 | doi = 10.3978/j.issn.2218-676X.2012.04.01 }} (As indicated in the article Genome instability, such genome instability may be due to deficiencies in other DNA repair genes present in the cancers.) Elevated DNA-PKcs is thought to be "beneficial to the tumor cells", though it would be at the expense of the patient. As indicated in a table listing 12 types of cancer reported in 20 publications, the fraction of cancers with over-expression of DNA-PKcs is often associated with an advanced stage of the cancer and shorter survival time for the patient. However, the table also indicates that for some cancers, the fraction of cancers with reduced or absent DNA-PKcs is also associated with advanced stage and poor patient survival.

Non-homologous end joining (NHEJ) is the principal DNA repair process used by mammalian somatic cells to cope with double-strand breaks that continually occur in the genome. DNA-PKcs is one of the key components of the NHEJ machinery. DNA-PKcs deficient mice have a shorter lifespan and show an earlier onset of numerous aging related pathologies than corresponding wild-type littermates.{{cite journal | vauthors = Espejel S, Martín M, Klatt P, Martín-Caballero J, Flores JM, Blasco MA | title = Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice | journal = EMBO Reports | volume = 5 | issue = 5 | pages = 503–9 | date = May 2004 | pmid = 15105825 | pmc = 1299048 | doi = 10.1038/sj.embor.7400127 }}{{cite journal | vauthors = Reiling E, Dollé ME, Youssef SA, Lee M, Nagarajah B, Roodbergen M, de With P, de Bruin A, Hoeijmakers JH, Vijg J, van Steeg H, Hasty P | title = The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency | journal = PLOS ONE | volume = 9 | issue = 4 | pages = e93568 | year = 2014 | pmid = 24740260 | pmc = 3989187 | doi = 10.1371/journal.pone.0093568 | doi-access = free | bibcode = 2014PLoSO...993568R }} These findings suggest that failure to efficiently repair DNA double-strand breaks results in premature aging, consistent with the DNA damage theory of aging. (See also Bernstein et al.{{cite book |vauthors=Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K |chapter=1. Cancer and aging as consequences of un-repaired DNA damage |chapter-url=https://web.archive.org/web/20141025091740/https://www.novapublishers.com/catalog/product_info.php?products_id=43247 |veditors=Kimura H, Suzuki A |title=New Research on DNA Damages |publisher=Nova Science |date=2008 |isbn=978-1-60456-581-2 |pages=1–47 }})

DNA-PKcs has been shown to interact with:

{{div col|colwidth=20em}}

• ATM,{{cite journal | vauthors = Suzuki K, Kodama S, Watanabe M | title = Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation | journal = The Journal of Biological Chemistry | volume = 274 | issue = 36 | pages = 25571–5 | date = September 1999 | pmid = 10464290 | doi = 10.1074/jbc.274.36.25571 | doi-access =free }}
• C1D, and
• CDC5L,{{cite journal | vauthors = Ajuh P, Kuster B, Panov K, Zomerdijk JC, Mann M, Lamond AI | title = Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry | journal = The EMBO Journal | volume = 19 | issue = 23 | pages = 6569–81 | date = December 2000 | pmid = 11101529 | pmc = 305846 | doi = 10.1093/emboj/19.23.6569 }}
• CHEK1,{{cite journal | vauthors = Kim ST, Lim DS, Canman CE, Kastan MB | title = Substrate specificities and identification of putative substrates of ATM kinase family members | journal = The Journal of Biological Chemistry | volume = 274 | issue = 53 | pages = 37538–43 | date = December 1999 | pmid = 10608806 | doi = 10.1074/jbc.274.53.37538 | doi-access = free }}{{cite journal | vauthors = Goudelock DM, Jiang K, Pereira E, Russell B, Sanchez Y | title = Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex | journal = The Journal of Biological Chemistry | volume = 278 | issue = 32 | pages = 29940–7 | date = August 2003 | pmid = 12756247 | doi = 10.1074/jbc.M301765200 | doi-access = free }}
• CHUK,{{cite journal | vauthors = Liu L, Kwak YT, Bex F, García-Martínez LF, Li XH, Meek K, Lane WS, Gaynor RB | title = DNA-dependent protein kinase phosphorylation of IkappaB alpha and IkappaB beta regulates NF-kappaB DNA binding properties | journal = Molecular and Cellular Biology | volume = 18 | issue = 7 | pages = 4221–34 | date = July 1998 | pmid = 9632806 | pmc = 109006 | doi = 10.1128/MCB.18.7.4221 | author8-link = Richard Gaynor }}
• CIB1,{{cite journal | vauthors = Wu X, Lieber MR | title = Interaction between DNA-dependent protein kinase and a novel protein, KIP | journal = Mutation Research | volume = 385 | issue = 1 | pages = 13–20 | date = October 1997 | pmid = 9372844 | doi = 10.1016/s0921-8777(97)00035-9 }}
• DCLRE1C,{{cite journal | vauthors = Ma Y, Pannicke U, Schwarz K, Lieber MR | title = Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination | journal = Cell | volume = 108 | issue = 6 | pages = 781–794 | date = March 2002 | pmid = 11955432 | doi = 10.1016/s0092-8674(02)00671-2 | doi-access = free }}
• ILF2,
• ILF3,{{cite journal | vauthors = Ting NS, Kao PN, Chan DW, Lintott LG, Lees-Miller SP | title = DNA-dependent protein kinase interacts with antigen receptor response element binding proteins NF90 and NF45 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 4 | pages = 2136–45 | date = January 1998 | pmid = 9442054 | doi = 10.1074/jbc.273.4.2136 | s2cid = 8781571 | doi-access = free | citeseerx = 10.1.1.615.1747 }}
• Ku80,{{cite journal | vauthors = Jin S, Kharbanda S, Mayer B, Kufe D, Weaver DT | title = Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit | journal = The Journal of Biological Chemistry | volume = 272 | issue = 40 | pages = 24763–6 | date = October 1997 | pmid = 9312071 | doi = 10.1074/jbc.272.40.24763 | doi-access =free }}{{cite journal | vauthors = Matheos D, Ruiz MT, Price GB, Zannis-Hadjopoulos M | title = Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1578 | issue = 1–3 | pages = 59–72 | date = October 2002 | pmid = 12393188 | doi = 10.1016/s0167-4781(02)00497-9 }}{{cite journal | vauthors = Gell D, Jackson SP | title = Mapping of protein-protein interactions within the DNA-dependent protein kinase complex | journal = Nucleic Acids Research | volume = 27 | issue = 17 | pages = 3494–3502 | date = September 1999 | pmid = 10446239 | pmc = 148593 | doi = 10.1093/nar/27.17.3494 }}
• NCOA6,{{cite journal | vauthors = Ko L, Cardona GR, Chin WW | title = Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 11 | pages = 6212–7 | date = May 2000 | pmid = 10823961 | pmc = 18584 | doi = 10.1073/pnas.97.11.6212 | doi-access = free | bibcode = 2000PNAS...97.6212K }}
• P53,{{cite journal | vauthors = Yavuzer U, Smith GC, Bliss T, Werner D, Jackson SP | title = DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D | journal = Genes & Development | volume = 12 | issue = 14 | pages = 2188–99 | date = July 1998 | pmid = 9679063 | pmc = 317006 | doi = 10.1101/gad.12.14.2188 }}
• RPA2,{{cite journal | vauthors = Shao RG, Cao CX, Zhang H, Kohn KW, Wold MS, Pommier Y | title = Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes | journal = The EMBO Journal | volume = 18 | issue = 5 | pages = 1397–1406 | date = March 1999 | pmid = 10064605 | pmc = 1171229 | doi = 10.1093/emboj/18.5.1397 }} and
• WRN.{{cite journal | vauthors = Karmakar P, Piotrowski J, Brosh RM, Sommers JA, Miller SP, Cheng WH, Snowden CM, Ramsden DA, Bohr VA | title = Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 21 | pages = 18291–302 | date = May 2002 | pmid = 11889123 | doi = 10.1074/jbc.M111523200 | doi-access = free }}

{{Div col end}}

AZD7648,{{cite journal | vauthors = Goldberg FW, Finlay MR, Ting AK, Beattie D, Lamont GM, Fallan C, Wrigley GL, Schimpl M, Howard MR, Williamson B, Vazquez-Chantada M, Barratt DG, Davies BR, Cadogan EB, Ramos-Montoya A, Dean E | title = The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor | journal = Journal of Medicinal Chemistry | volume = 63 | issue = 7 | pages = 3461–3471 | date = April 2020 | pmid = 31851518 | doi = 10.1021/acs.jmedchem.9b01684 | doi-access = free }} M3814 (peposertib),{{Cite journal |title=Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models |url=https://aacrjournals.org/mct/article/19/5/1091/92835/Pharmacologic-Inhibitor-of-DNA-PK-M3814 |journal=Molecular Cancer Therapeutics}} M9831 (VX-984){{cite journal | vauthors = Khan AJ, Misenko SM, Thandoni A, Schiff D, Jhawar SR, Bunting SF, Haffty BG | title = VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells | journal = Oncotarget | volume = 9 | issue = 40 | pages = 25833–25841 | date = May 2018 | pmid = 29899825 | pmc = 5995231 | doi = 10.18632/oncotarget.25383 }} and BAY-8400{{cite journal | vauthors = Berger M, Wortmann L, Buchgraber P, Lücking U, Zitzmann-Kolbe S, Wengner AM, Bader B, Bömer U, Briem H, Eis K, Rehwinkel H, Bartels F, Moosmayer D, Eberspächer U, Lienau P, Hammer S, Schatz CA, Wang Q, Wang Q, Mumberg D, Nising CF, Siemeister G | title = BAY-8400: A Novel Potent and Selective DNA-PK Inhibitor which Shows Synergistic Efficacy in Combination with Targeted Alpha Therapies | journal = Journal of Medicinal Chemistry | volume = 64 | issue = 17 | pages = 12723–12737 | date = September 2021 | pmid = 34428039 | doi = 10.1021/acs.jmedchem.1c00762 | doi-access = free }} have been described as potent and selective DNA-PKcs inhibitors.

• Non-homologous end joining
• V(D)J recombination
• Ku
• Protein kinase

{{Reflist}}

{{Serine/threonine-specific protein kinases}}

{{Enzymes}}

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Category:EC 2.7.11