DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) is an enzyme that in humans is encoded by the PRKDC gene. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. 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. DNA-PKcs is required for the non-homologous end joining (NHEJ) pathway of DNA repair. 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. DNA-PK also cooperates with ATR and ATM to phosphorylate proteins involved in the DNA damage checkpoint.
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A synthetic inhibitor of DNA-PK also inhibits mTOR (IC50=5.3 uM); no inhibition on p110α/p85α PI3K (>100 uM); blocks the phosphorylation of S6 kinase 1 Thr389 and Akt Ser473 in COS7 cells.
VX-984 (M 9831) is a potent, selective inhibitor of DNA-PK with IC50 of 88±64 nM for inhibition of DNA-PKcs autophosphorylation (Ser2056) in A549 lung cancer cells, with good selectivity versus other PI3K family members.
IC 86621 is a potent DNA-PK inhibitor with IC50 of 135 nM, also inhibits p110β (IC50=135 nM), less potent for p110α/γ/δ (IC50=880-1,400 nM); directly inhibits the repair of DNA DSBs and consequently enhances the cytotoxicity of physical and chemical agents that induce DSBs but not other DNA lesions.
IC 87361 is a potent and selective DNA-PK inhibitor with IC50 of 34 nM, shows >50-fold selectivity over p110β; enhances radiation sensitivity in wild-type C57BL6 endothelial cells; induces radiosensitization of tumor microvasculature in wild-type mice.
A poten and selective, ATP-competitive DNA-PK inhibitor with IC50 of 0.19 uM, Ki of 24 nM; exhibits selectivity for DNA-PK versus related enzymes ATM, ATR, mTOR, and p110α; sensitizes the HeLa cells to the cytotoxic effects of ionizing radiation in vitro.
SU-11752 is a potent, selective inhibitor of DNA-PK, >500-fold selectivity over PI3Kγ, inhibits DNA double-strand break repair in cells and sensitizs ionizing radiation in cancer cells.
KU-006064 is a potent, dual inhibitor of DNA-PK (IC50=8.6 nM) and PI3K (IC50=4/0.5/0.1 nM for PI3Kα/β/δ); shows selectively over other PI-3K-like kinases, such as ATM, ATR and mTOR; inhibits cellular DNA-PK autophosphorylation with IC50 of 19 nM (MCF7 cells) and 170 nM (SW620 cells); reduces the frequency of NHEJ while increasing the rate of HDR following Cas9-mediated DNA cleavage.
AZD-7648 is a potent and selective DNA-PK inhibitor. Anti-tumor activity.
PIK-75 is a potent, isoform-selective p110α inhibitor with IC50 of 0.3 nM, displays >100-fold selectivity over p110β, p110δ and PI3K C2b; blocks the phosphorylation of PKB induced by insulin on both Ser473 and Thr308 in CHO-IR cell (IC50=78 nM), inhibits PI3K activation associated with dramatic suppression of downstream signaling events, including AKT phosphorylation, IKK activation, and NF-kappaB transcription; potently and dose dependently inhibits in vitro and in vivo production of TNF-alpha and IL-6, diminishes the induced expression of human endothelial cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), and blocks human monocyte-endothelial cell adhesion; exhibits significant anti-tumor effectiveness in vivo.
Afatinib is a highly potent and selective DNA-PK inhibitor (IC50=14 nM); also modestly inhibits BRD4 and BRDT with IC50 of 1 uM and 3.5 uM respectively; also stimulates Cas9-mediated genome editing.
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