PRKDC
Identifiers
AliasesPRKDC, DNA-PKcs, DNAPK, DNPK1, HYRC, HYRC1, XRCC7, p350, IMD26, protein kinase, DNA-activated, catalytic polypeptide, DNA-PKC, protein kinase, DNA-activated, catalytic subunit, DNAPKc
External IDsOMIM: 600899 MGI: 104779 HomoloGene: 5037 GeneCards: PRKDC
Orthologs
SpeciesHumanMouse
Entrez

5591

19090

Ensembl

ENSG00000253729

ENSMUSG00000022672

UniProt

P78527

P97313

RefSeq (mRNA)

NM_001081640
NM_006904

NM_011159

RefSeq (protein)

NP_001075109
NP_008835

NP_035289

Location (UCSC)Chr 8: 47.77 – 47.96 MbChr 16: 15.46 – 15.66 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the gene designated as PRKDC or XRCC7.[5] DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. The DNA-Pkcs protein is a serine/threonine protein kinase consisting of a single polypeptide chain of 4,128 amino acids.[6][7]

Function

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.[8] 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.[9] DNA-PK also cooperates with ATR and ATM to phosphorylate proteins involved in the DNA damage checkpoint.

Disease

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.[10] Human SCID usually have other causes, but two cases related to mutations in this gene are also known.[11]

Cancer

DNA damage appears to be the primary underlying cause of cancer,[12] and deficiencies in DNA repair genes likely underlie many forms of cancer.[13][14] 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.[15][16] 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.[17] They were also found in 10% of breast and pancreatic cancers.[18]

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. DNA-PKcs expression was reduced by 23% to 57% in six cancers as indicated in the table.

Frequency of reduced expression of DNA-PKcs in sporadic cancers
CancerFrequency of reduction in cancerRef.
Breast cancer57%[19]
Prostate cancer51%[20]
Cervical carcinoma32%[21]
Nasopharyngeal carcinoma30%[22]
Epithelial ovarian cancer29%[23]
Gastric cancer23%[24]

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.[25] But miR-101 is more often decreased in cancers, rather than increased.[26][27]

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.[28] The let-7a microRNA normally represses the HMGA2 gene.[29][30] 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.[31] 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.[32] After ionizing radiation DNA-PKcs was increased in the surviving cells of oral squamous cell carcinoma tissues.[33]

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).[34] 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.[35] (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",[35] though it would be at the expense of the patient. As indicated in a table listing 12 types of cancer reported in 20 publications,[35] 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.

Aging

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.[36][37] 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.[38])

Interactions

DNA-PKcs has been shown to interact with:

DNA-PKcs Inhibitors

AZD7648,[54] M3814 (peposertib),[55] M9831 (VX-984)[56] and BAY-8400[57] have been described as potent and selective DNA-PKcs inhibitors.

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000253729 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022672 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Sipley JD, Menninger JC, Hartley KO, Ward DC, Jackson SP, Anderson CW (August 1995). "Gene for the catalytic subunit of the human DNA-activated protein kinase maps to the site of the XRCC7 gene on chromosome 8". Proceedings of the National Academy of Sciences of the United States of America. 92 (16): 7515–7519. Bibcode:1995PNAS...92.7515S. doi:10.1073/pnas.92.16.7515. PMC 41370. PMID 7638222.
  6. ↑ Sibanda BL, Chirgadze DY, Blundell TL (January 2010). "Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats". Nature. 463 (7277): 118–121. doi:10.1038/nature08648. PMC 2811870. PMID 20023628.
  7. ↑ Hartley KO, Gell D, Smith GC, Zhang H, Divecha N, Connelly MA, et al. (September 1995). "DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product". Cell. 82 (5): 849–856. doi:10.1016/0092-8674(95)90482-4. PMID 7671312.
  8. ↑ "Entrez Gene: PRKDC protein kinase, DNA-activated, catalytic polypeptide".
  9. ↑ Meek K, Dang V, Lees-Miller SP (2008). Chapter 2 DNA-PK. Advances in Immunology. Vol. 99. pp. 33–58. doi:10.1016/S0065-2776(08)00602-0. ISBN 9780123743251. PMID 19117531.
  10. ↑ Meek K, Jutkowitz A, Allen L, Glover J, Convery E, Massa A, et al. (August 2009). "SCID dogs: similar transplant potential but distinct intra-uterine growth defects and premature replicative senescence compared with SCID mice". Journal of Immunology. 183 (4): 2529–2536. doi:10.4049/jimmunol.0801406. PMC 4047667. PMID 19635917.
  11. ↑ Anne Esguerra Z, Watanabe G, Okitsu CY, Hsieh CL, Lieber MR (April 2020). "DNA-PKcs chemical inhibition versus genetic mutation: Impact on the junctional repair steps of V(D)J recombination". Molecular Immunology. 120: 93–100. doi:10.1016/j.molimm.2020.01.018. PMC 7184946. PMID 32113132.
  12. ↑ Kastan MB (April 2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Molecular Cancer Research. 6 (4): 517–524. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632.
  13. ↑ Harper JW, Elledge SJ (December 2007). "The DNA damage response: ten years after". Molecular Cell. 28 (5): 739–745. doi:10.1016/j.molcel.2007.11.015. PMID 18082599.
  14. ↑ Dietlein F, Reinhardt HC (December 2014). "Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy". Clinical Cancer Research. 20 (23): 5882–5887. doi:10.1158/1078-0432.CCR-14-1165. PMID 25451105.
  15. ↑ O'Hagan HM, Mohammad HP, Baylin SB (August 2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLOS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159.
  16. ↑ Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, et al. (July 2007). "DNA damage, homology-directed repair, and DNA methylation". PLOS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978.
  17. ↑ Er TK, Su YF, Wu CC, Chen CC, Wang J, Hsieh TH, et al. (July 2016). "Targeted next-generation sequencing for molecular diagnosis of endometriosis-associated ovarian cancer". Journal of Molecular Medicine. 94 (7): 835–847. doi:10.1007/s00109-016-1395-2. PMID 26920370. S2CID 16399834.
  18. ↑ Wang X, Szabo C, Qian C, Amadio PG, Thibodeau SN, Cerhan JR, et al. (February 2008). "Mutational analysis of thirty-two double-strand DNA break repair genes in breast and pancreatic cancers". Cancer Research. 68 (4): 971–975. doi:10.1158/0008-5472.CAN-07-6272. PMID 18281469.
  19. ↑ Söderlund Leifler K, Queseth S, Fornander T, Askmalm MS (December 2010). "Low expression of Ku70/80, but high expression of DNA-PKcs, predict good response to radiotherapy in early breast cancer". International Journal of Oncology. 37 (6): 1547–1554. doi:10.3892/ijo_00000808. PMID 21042724.
  20. ↑ Bouchaert P, Guerif S, Debiais C, Irani J, Fromont G (December 2012). "DNA-PKcs expression predicts response to radiotherapy in prostate cancer". International Journal of Radiation Oncology, Biology, Physics. 84 (5): 1179–1185. doi:10.1016/j.ijrobp.2012.02.014. PMID 22494583.
  21. ↑ Zhuang L, Yu SY, Huang XY, Cao Y, Xiong HH (July 2007). "[Potentials of DNA-PKcs, Ku80, and ATM in enhancing radiosensitivity of cervical carcinoma cells]". AI Zheng = Aizheng = Chinese Journal of Cancer (in Chinese). 26 (7): 724–729. PMID 17626748.
  22. ↑ Lee SW, Cho KJ, Park JH, Kim SY, Nam SY, Lee BJ, et al. (August 2005). "Expressions of Ku70 and DNA-PKcs as prognostic indicators of local control in nasopharyngeal carcinoma". International Journal of Radiation Oncology, Biology, Physics. 62 (5): 1451–1457. doi:10.1016/j.ijrobp.2004.12.049. PMID 16029807.
  23. ↑ Abdel-Fatah TM, Arora A, Moseley P, Coveney C, Perry C, Johnson K, et al. (December 2014). "ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers". BBA Clinical. 2: 10–17. doi:10.1016/j.bbacli.2014.08.001. PMC 4633921. PMID 26674120.
  24. ↑ Lee HS, Yang HK, Kim WH, Choe G (April 2005). "Loss of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in gastric cancers". Cancer Research and Treatment. 37 (2): 98–102. doi:10.4143/crt.2005.37.2.98. PMC 2785401. PMID 19956487.
  25. ↑ Yan D, Ng WL, Zhang X, Wang P, Zhang Z, Mo YY, et al. (July 2010). "Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation". PLOS ONE. 5 (7): e11397. Bibcode:2010PLoSO...511397Y. doi:10.1371/journal.pone.0011397. PMC 2895662. PMID 20617180.
  26. ↑ Li M, Tian L, Ren H, Chen X, Wang Y, Ge J, et al. (August 2015). "MicroRNA-101 is a potential prognostic indicator of laryngeal squamous cell carcinoma and modulates CDK8". Journal of Translational Medicine. 13: 271. doi:10.1186/s12967-015-0626-6. PMC 4545549. PMID 26286725.
  27. ↑ Liu Z, Wang J, Mao Y, Zou B, Fan X (January 2016). "MicroRNA-101 suppresses migration and invasion via targeting vascular endothelial growth factor-C in hepatocellular carcinoma cells". Oncology Letters. 11 (1): 433–438. doi:10.3892/ol.2015.3832. PMC 4727073. PMID 26870229.
  28. ↑ Li AY, Boo LM, Wang SY, Lin HH, Wang CC, Yen Y, et al. (July 2009). "Suppression of nonhomologous end joining repair by overexpression of HMGA2". Cancer Research. 69 (14): 5699–5706. doi:10.1158/0008-5472.CAN-08-4833. PMC 2737594. PMID 19549901.
  29. ↑ Motoyama K, Inoue H, Nakamura Y, Uetake H, Sugihara K, Mori M (April 2008). "Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family". Clinical Cancer Research. 14 (8): 2334–2340. doi:10.1158/1078-0432.CCR-07-4667. PMID 18413822.
  30. ↑ Wu A, Wu K, Li J, Mo Y, Lin Y, Wang Y, et al. (March 2015). "Let-7a inhibits migration, invasion and epithelial-mesenchymal transition by targeting HMGA2 in nasopharyngeal carcinoma". Journal of Translational Medicine. 13: 105. doi:10.1186/s12967-015-0462-8. PMC 4391148. PMID 25884389.
  31. ↑ Vrba L, Muñoz-Rodríguez JL, Stampfer MR, Futscher BW (2013). "miRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer". PLOS ONE. 8 (1): e54398. Bibcode:2013PLoSO...854398V. doi:10.1371/journal.pone.0054398. PMC 3547033. PMID 23342147.
  32. ↑ Lee HS, Choe G, Park KU, Park DJ, Yang HK, Lee BL, Kim WH (October 2007). "Altered expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) during gastric carcinogenesis and its clinical implications on gastric cancer". International Journal of Oncology. 31 (4): 859–866. doi:10.3892/ijo.31.4.859. PMID 17786318.
  33. ↑ Shintani S, Mihara M, Li C, Nakahara Y, Hino S, Nakashiro K, Hamakawa H (October 2003). "Up-regulation of DNA-dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma". Cancer Science. 94 (10): 894–900. doi:10.1111/j.1349-7006.2003.tb01372.x. PMID 14556663. S2CID 2126685.
  34. ↑ Riabinska A, Daheim M, Herter-Sprie GS, Winkler J, Fritz C, Hallek M, et al. (June 2013). "Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors". Science Translational Medicine. 5 (189): 189ra78. doi:10.1126/scitranslmed.3005814. PMID 23761041. S2CID 206681916.
  35. 1 2 3 Hsu FM, Zhang S, Chen BP (June 2012). "Role of DNA-dependent protein kinase catalytic subunit in cancer development and treatment". Translational Cancer Research. 1 (1): 22–34. doi:10.3978/j.issn.2218-676X.2012.04.01. PMC 3431019. PMID 22943041.
  36. ↑ Espejel S, Martín M, Klatt P, Martín-Caballero J, Flores JM, Blasco MA (May 2004). "Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice". EMBO Reports. 5 (5): 503–509. doi:10.1038/sj.embor.7400127. PMC 1299048. PMID 15105825.
  37. ↑ Reiling E, Dollé ME, Youssef SA, Lee M, Nagarajah B, Roodbergen M, et al. (2014). "The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency". PLOS ONE. 9 (4): e93568. Bibcode:2014PLoSO...993568R. doi:10.1371/journal.pone.0093568. PMC 3989187. PMID 24740260.
  38. ↑ Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 Archived 2014-10-25 at the Wayback Machine ISBN 978-1604565812
  39. 1 2 3 4 Kim ST, Lim DS, Canman CE, Kastan MB (December 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". The Journal of Biological Chemistry. 274 (53): 37538–37543. doi:10.1074/jbc.274.53.37538. PMID 10608806.
  40. ↑ Suzuki K, Kodama S, Watanabe M (September 1999). "Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation". The Journal of Biological Chemistry. 274 (36): 25571–25575. doi:10.1074/jbc.274.36.25571. PMID 10464290.
  41. 1 2 Yavuzer U, Smith GC, Bliss T, Werner D, Jackson SP (July 1998). "DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D". Genes & Development. 12 (14): 2188–2199. doi:10.1101/gad.12.14.2188. PMC 317006. PMID 9679063.
  42. ↑ Ajuh P, Kuster B, Panov K, Zomerdijk JC, Mann M, Lamond AI (December 2000). "Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry". The EMBO Journal. 19 (23): 6569–6581. doi:10.1093/emboj/19.23.6569. PMC 305846. PMID 11101529.
  43. 1 2 Goudelock DM, Jiang K, Pereira E, Russell B, Sanchez Y (August 2003). "Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex". The Journal of Biological Chemistry. 278 (32): 29940–29947. doi:10.1074/jbc.M301765200. PMID 12756247.
  44. ↑ Liu L, Kwak YT, Bex F, García-Martínez LF, Li XH, Meek K, et al. (July 1998). "DNA-dependent protein kinase phosphorylation of IkappaB alpha and IkappaB beta regulates NF-kappaB DNA binding properties". Molecular and Cellular Biology. 18 (7): 4221–4234. doi:10.1128/MCB.18.7.4221. PMC 109006. PMID 9632806.
  45. ↑ Wu X, Lieber MR (October 1997). "Interaction between DNA-dependent protein kinase and a novel protein, KIP". Mutation Research. 385 (1): 13–20. doi:10.1016/s0921-8777(97)00035-9. PMID 9372844.
  46. ↑ Ma Y, Pannicke U, Schwarz K, Lieber MR (March 2002). "Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination". Cell. 108 (6): 781–794. doi:10.1016/s0092-8674(02)00671-2. PMID 11955432.
  47. 1 2 Ting NS, Kao PN, Chan DW, Lintott LG, Lees-Miller SP (January 1998). "DNA-dependent protein kinase interacts with antigen receptor response element binding proteins NF90 and NF45". The Journal of Biological Chemistry. 273 (4): 2136–2145. CiteSeerX 10.1.1.615.1747. doi:10.1074/jbc.273.4.2136. PMID 9442054. S2CID 8781571.
  48. ↑ Jin S, Kharbanda S, Mayer B, Kufe D, Weaver DT (October 1997). "Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit". The Journal of Biological Chemistry. 272 (40): 24763–24766. doi:10.1074/jbc.272.40.24763. PMID 9312071.
  49. ↑ Matheos D, Ruiz MT, Price GB, Zannis-Hadjopoulos M (October 2002). "Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1578 (1–3): 59–72. doi:10.1016/s0167-4781(02)00497-9. PMID 12393188.
  50. ↑ Gell D, Jackson SP (September 1999). "Mapping of protein-protein interactions within the DNA-dependent protein kinase complex". Nucleic Acids Research. 27 (17): 3494–3502. doi:10.1093/nar/27.17.3494. PMC 148593. PMID 10446239.
  51. ↑ Ko L, Cardona GR, Chin WW (May 2000). "Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 6212–6217. Bibcode:2000PNAS...97.6212K. doi:10.1073/pnas.97.11.6212. PMC 18584. PMID 10823961.
  52. ↑ Shao RG, Cao CX, Zhang H, Kohn KW, Wold MS, Pommier Y (March 1999). "Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes". The EMBO Journal. 18 (5): 1397–1406. doi:10.1093/emboj/18.5.1397. PMC 1171229. PMID 10064605.
  53. ↑ Karmakar P, Piotrowski J, Brosh RM, Sommers JA, Miller SP, Cheng WH, et al. (May 2002). "Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation". The Journal of Biological Chemistry. 277 (21): 18291–18302. doi:10.1074/jbc.M111523200. PMID 11889123.
  54. ↑ 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 (2020). "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 of Medicinal Chemistry. 63 (7): 3461–3471. doi:10.1021/acs.jmedchem.9b01684. PMID 31851518.
  55. ↑ "Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models". Molecular Cancer Therapeutics.
  56. ↑ Khan AJ, Misenko SM, Thandoni A, Schiff D, Jhawar SR, Bunting SF, Haffty BG (2018). "VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells". Oncotarget. 9 (40): 25833–25841. doi:10.18632/oncotarget.25383. PMC 5995231. PMID 29899825.
  57. ↑ 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 (2021). "BAY-8400: A Novel Potent and Selective DNA-PK Inhibitor which Shows Synergistic Efficacy in Combination with Targeted Alpha Therapies". Journal of Medicinal Chemistry. 64 (17): 12723–12737. doi:10.1021/acs.jmedchem.1c00762. PMID 34428039.
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