protein kinase, DNA-activated, catalytic subunit | Other PIKK family kinases | IUPHAR Guide to IMMUNOPHARMACOLOGY

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protein kinase, DNA-activated, catalytic subunit

  Target has curated data in GtoImmuPdb

Target id: 2800

Nomenclature: protein kinase, DNA-activated, catalytic subunit

Family: Other PIKK family kinases

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 4128 8q11 PRKDC protein kinase, DNA-activated, catalytic subunit
Mouse - 4128 16 B1 Prkdc protein kinase, DNA activated, catalytic polypeptide
Rat - - 11q23 Prkdc protein kinase
Gene and Protein Information Comments
Isoform 1 of the human protein is the 4128 amino acid form in the table above. A second isoform, isoform 2 (NP_001075109), has also been reported and this has 4097 amino acids.
Previous and Unofficial Names
DNA-dependent protein kinase catalytic subunit | protein kinase | protein kinase, DNA activated, catalytic polypeptide | protein kinase, DNA-activated, catalytic polypeptide
Database Links
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Parameter Reference
compound 82 [PMID: 21332118] Hs Inhibition 8.5 pKi 4
pKi 8.5 (Ki 3x10-9 M) [4]
wortmannin Hs Inhibition 6.9 pKi 5
pKi 6.9 (Ki 1.2x10-7 M) [5]
torin 2 Hs Inhibition 9.3 pIC50 10
pIC50 9.3 (IC50 5x10-10 M) [10]
PIK-75 Hs Inhibition 8.7 pIC50 8
pIC50 8.7 (IC50 2x10-9 M) [8]
M-3814 Hs Inhibition >8.5 pIC50 6
pIC50 >8.5 (IC50 <3x10-9 M) [6]
KU-0060648 Hs Inhibition 8.3 pIC50 3
pIC50 8.3 (IC50 5x10-9 M) [3]
NU-7441 Hs Inhibition 7.8 pIC50 9
pIC50 7.8 (IC50 1.4x10-8 M) [9]
Description: ELISA measuring the ability of DNA-PK (extracted from HeLa cells) to phosphorylate Ser15 of a p53 peptide
PI-103 Hs Inhibition 7.6 pIC50 11
pIC50 7.6 (IC50 2.3x10-8 M) [11]
PP121 Hs Inhibition 7.2 pIC50 1
pIC50 7.2 (IC50 6x10-8 M) [1]
DNA-PK inhibitor III Mm Inhibition 6.9 pIC50 5
pIC50 6.9 (IC50 1.2x10-7 M) [5]
Description: Inhibition of PRKDC in C57BL6 mouse endothelial cells
NU-7026 Hs Inhibition 6.6 pIC50 7
pIC50 6.6 (IC50 2.3x10-7 M) [7]
DNA-PK inhibitor V Hs Inhibition 6.6 pIC50 2
pIC50 6.6 (IC50 2.7x10-7 M) [2]
View species-specific inhibitor tables
Immunopharmacology Comments
Protein kinase, DNA-activated, catalytic polypeptide (DNA-PKcs) principally acts to repair DNA in a process called non-homologous end joining (NHEJ). NHEJ is required for V(D)J recombination (somatic recombination) in developing lymphocytes during the early stages of T and B cell maturation. DNA-PKcs knockout mice develop severe combined immunodeficiency as NHEJ is compromised and they are unable to construct the huge repertoire of antibodies and T cell receptors necessary for a fully developed adaptive immune response.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0002218 activation of innate immune response IDA
click arrow to show/hide IEA associations
GO:0045087 innate immune response IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0032481 positive regulation of type I interferon production TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 5 GO processes
GO:0016567 protein ubiquitination TAS
click arrow to show/hide IEA associations
GO:0002326 B cell lineage commitment IEA
GO:0002360 T cell lineage commitment IEA
GO:0033077 T cell differentiation in thymus IEA
GO:0033153 T cell receptor V(D)J recombination IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 3 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002360 T cell lineage commitment IEA
GO:0033077 T cell differentiation in thymus IEA
GO:0033153 T cell receptor V(D)J recombination IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002326 B cell lineage commitment IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 2 GO processes, IEA only
GO:0002218 activation of innate immune response IDA
click arrow to show/hide IEA associations
GO:0002638 negative regulation of immunoglobulin production IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 8 GO processes, IEA only
GO:0033152 immunoglobulin V(D)J recombination IBA
click arrow to show/hide IEA associations
GO:0002326 B cell lineage commitment IEA
GO:0002328 pro-B cell differentiation IEA
GO:0002360 T cell lineage commitment IEA
GO:0033077 T cell differentiation in thymus IEA
GO:0033153 T cell receptor V(D)J recombination IEA
GO:0048536 spleen development IEA
GO:0048538 thymus development IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Immunodeficiency 26 with or without neurologic abnormalities; IMD26
Synonyms: Severe combined immunodeficiency due to DNA-PKcs deficiency [Orphanet: ORPHA317425]
OMIM: 615966
Orphanet: ORPHA317425

References

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1. Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM, Knight ZA. (2008) Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat. Chem. Biol., 4 (11): 691-9. [PMID:18849971]

2. Ballou LM, Selinger ES, Choi JY, Drueckhammer DG, Lin RZ. (2007) Inhibition of mammalian target of rapamycin signaling by 2-(morpholin-1-yl)pyrimido[2,1-alpha]isoquinolin-4-one. J. Biol. Chem., 282 (33): 24463-70. [PMID:17562705]

3. Cano C, Saravanan K, Bailey C, Bardos J, Curtin NJ, Frigerio M, Golding BT, Hardcastle IR, Hummersone MG, Menear KA et al.. (2013) 1-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity. J. Med. Chem., 56 (16): 6386-401. [PMID:23855836]

4. D'Angelo ND, Kim TS, Andrews K, Booker SK, Caenepeel S, Chen K, D'Amico D, Freeman D, Jiang J, Liu L et al.. (2011) Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors. J. Med. Chem., 54 (6): 1789-811. [PMID:21332118]

5. Finlay MR, Griffin RJ. (2012) Modulation of DNA repair by pharmacological inhibitors of the PIKK protein kinase family. Bioorg. Med. Chem. Lett., 22 (17): 5352-9. [PMID:22835870]

6. Fuchss T, Ulrich E, Buchstakker H-P, Werner M. (2016) Arylquinazolines. Patent number: WO2014183850. Assignee: Merck Patent Gmbh. Priority date: 11/05/2013. Publication date: 24/03/2016.

7. Hollick JJ, Golding BT, Hardcastle IR, Martin N, Richardson C, Rigoreau LJ, Smith GC, Griffin RJ. (2003) 2,6-disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK). Bioorg. Med. Chem. Lett., 13 (18): 3083-6. [PMID:12941339]

8. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B et al.. (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell, 125 (4): 733-47. [PMID:16647110]

9. Leahy JJ, Golding BT, Griffin RJ, Hardcastle IR, Richardson C, Rigoreau L, Smith GC. (2004) Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries. Bioorg. Med. Chem. Lett., 14 (24): 6083-7. [PMID:15546735]

10. Liu Q, Wang J, Kang SA, Thoreen CC, Hur W, Ahmed T, Sabatini DM, Gray NS. (2011) Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J. Med. Chem., 54 (5): 1473-80. [PMID:21322566]

11. Raynaud FI, Eccles SA, Patel S, Alix S, Box G, Chuckowree I, Folkes A, Gowan S, De Haven Brandon A, Di Stefano F et al.. (2009) Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol. Cancer Ther., 8 (7): 1725-38. [PMID:19584227]

How to cite this page

Other PIKK family kinases: protein kinase, DNA-activated, catalytic subunit. Last modified on 27/06/2018. Accessed on 25/05/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2800.