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protein kinase, DNA-activated, catalytic subunit

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 2800

Nomenclature: protein kinase, DNA-activated, catalytic subunit

Family: Other PIKK family kinases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 4128 8q11.21 PRKDC protein kinase, DNA-activated, catalytic subunit
Mouse - 4128 16 A2 Prkdc protein kinase, DNA activated, catalytic polypeptide
Rat - - 11q23 Prkdc protein kinase, DNA-activated, catalytic subunit
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 Click here for help
DNA-dependent protein kinase catalytic subunit | protein kinase | protein kinase, DNA activated, catalytic polypeptide | protein kinase, DNA-activated, catalytic polypeptide | DNA-PK | DNA-PKcs
Database Links Click here for help
Alphafold P78527 (Hs), P97313 (Mm)
CATH/Gene3D 1.10.1070.11, 1.25.10.10, 1.25.40.10
ChEMBL Target CHEMBL3142 (Hs), CHEMBL2176779 (Mm)
Ensembl Gene ENSG00000253729 (Hs), ENSMUSG00000022672 (Mm), ENSRNOG00000025028 (Rn)
Entrez Gene 5591 (Hs), 19090 (Mm), 360748 (Rn)
Human Protein Atlas ENSG00000253729 (Hs)
KEGG Gene hsa:5591 (Hs), mmu:19090 (Mm), rno:360748 (Rn)
OMIM 600899 (Hs)
Pharos P78527 (Hs)
RefSeq Nucleotide NM_006904 (Hs), NM_001081640 (Hs), NM_011159 (Mm)
RefSeq Protein NP_001075109 (Hs), NP_008835 (Hs), NP_035289 (Mm)
UniProtKB P78527 (Hs), P97313 (Mm)
Wikipedia PRKDC (Hs)
Substrates and Reaction Kinetics Click here for help
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
cofilin 2 Substrate is endogenous in the given species Mm - - 6

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 82 [PMID: 21332118] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.5 pKi 5
⤷ pKi 8.5 (Ki 3x10-9 M) [5]
wortmannin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.9 pKi 7
⤷ pKi 6.9 (Ki 1.2x10-7 M) [7]
torin 2 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.3 pIC50 15
⤷ pIC50 9.3 (IC50 5x10-10 M) [15]
XRD-0394 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.2 pIC50 8
⤷ pIC50 9.2 (IC50 6.3x10-10 M) [8]
PIK-75 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.7 pIC50 13
⤷ pIC50 8.7 (IC50 2x10-9 M) [13]
peposertib Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition >8.5 pIC50 10
⤷ pIC50 >8.5 (IC50 <3x10-9 M) [10]
KU-0060648 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.3 pIC50 4
⤷ pIC50 8.3 (IC50 5x10-9 M) [4]
AZD7648 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.0 – 9.2 pIC50 11
⤷ pIC50 9.2 (IC50 6.3x10-10 M) [11]
Description: Measured by time-resolved fluorescence (TR-FRET) in a biochemical assay.
pIC50 7.0 (IC50 9.1x10-8 M) [11]
Description: Measuring inhibition of irradiation-induced DNA-PK autophosphorylation in A549 cells by ELISA.
NU-7441 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.8 pIC50 14
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [14]
Description: ELISA measuring the ability of DNA-PK (extracted from HeLa cells) to phosphorylate Ser15 of a p53 peptide
PI-103 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.6 pIC50 16
⤷ pIC50 7.6 (IC50 2.3x10-8 M) [16]
PP121 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.2 pIC50 1
⤷ pIC50 7.2 (IC50 6x10-8 M) [1]
BAY-8400 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 pIC50 3
⤷ pIC50 7.1 (IC50 8.1x10-8 M) [3]
DNA-PK inhibitor III Small molecule or natural product Primary target of this compound Mm Inhibition 6.9 pIC50 7
⤷ pIC50 6.9 (IC50 1.2x10-7 M) [7]
Description: Inhibition of PRKDC in C57BL6 mouse endothelial cells
NU-7026 Small molecule or natural product Primary target of this compound Hs Inhibition 6.6 pIC50 12
⤷ pIC50 6.6 (IC50 2.3x10-7 M) [12]
DNA-PK inhibitor V Small molecule or natural product Primary target of this compound Hs Inhibition 6.6 pIC50 2
⤷ pIC50 6.6 (IC50 2.7x10-7 M) [2]
lartesertib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.2 pIC50 9
⤷ pIC50 6.2 (IC50 6x10-7 M) [9]
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
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Immunodeficiency 26 with or without neurologic abnormalities; IMD26
Synonyms: Severe combined immunodeficiency due to DNA-PKcs deficiency [Orphanet: ORPHA317425]
OMIM: 615966
Orphanet: ORPHA317425
General Comments
DNA-PKcs promotes endothelial dysfunction and myocardial microvascular damage in response to endotoxemia via phosphorylation of Thr25 of cofilin 2 (CFL2) which in turn leads to F-actin depolymerisation, loss of endothelial barrier integrity and microvascular inflammation [6].

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. Berger M, Wortmann L, Buchgraber P, Lücking U, Zitzmann-Kolbe S, Wengner AM, Bader B, Bömer U, Briem H, Eis K et al.. (2021) BAY-8400: A Novel Potent and Selective DNA-PK Inhibitor which Shows Synergistic Efficacy in Combination with Targeted Alpha Therapies. J Med Chem, 64 (17): 12723-12737. [PMID:34428039]

4. 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]

5. 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]

6. Du Y, Zhu P, Li Y, Yu J, Xia T, Chang X, Zhu H, Li R, He Q. (2024) DNA-PKcs Phosphorylates Cofilin2 to Induce Endothelial Dysfunction and Microcirculatory Disorder in Endotoxemic Cardiomyopathy. Research (Wash D C), 7: 0331. [PMID:38550779]

7. 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]

8. Fu J, Wang Y, Sun Y, Wu G, Lu A, Zhang S, Goodnow RA, Gilmer T, Kastan M, Kirsch D. (2021) Dual atm and dna-pk inhibitors for use in anti-tumor therapy. Patent number: WO2021022078A1. Assignee: Xrad Therapeutics, Inc.. Priority date: 30/07/2020. Publication date: 04/02/2021.

9. Fuchas T, Becker A, Kubas H, Graedler U. (2020) Imidazolonylquinoline compounds and therapeutic uses thereof. Patent number: WO2020193660A1. Assignee: Merck Patent Gmbh. Priority date: 25/03/2020. Publication date: 01/10/2020.

10. 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.

11. Goldberg FW, Finlay MRV, Ting AKT, Beattie D, Lamont GM, Fallan C, Wrigley GL, Schimpl M, Howard MR, Williamson B et al.. (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. J Med Chem, 63 (7): 3461-3471. [PMID:31851518]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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 18/07/2024. Accessed on 14/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2800.