DNA-PK

PI3K/Akt/mTOR

• All (19)
• DNA-PK Inhibitors (19)
• New DNA-PK Products

Cat.No.	Product Name	Information	Product Use Citations	Product Validations
S2638	NU7441 (KU-57788)	NU7441 (KU-57788) is a highly potent and selective DNA-PK inhibitor with IC50 of 14 nM. It also inhibits mTOR and PI3K with IC50 of 1.7 μM and 5 μM in cell-free assays, respectively, and reduces the frequency of NHEJ while increasing the rate of HDR following Cas9-mediated DNA cleavage.	Nat Cell Biol, 2025, 27(1):59-72 Trends Biotechnol, 2025, S0167-7799(25)00314-2 Nat Commun, 2025, 16(1):997
S2893	NU7026	NU7026 (LY293646) is a potent DNA-PK inhibitor with IC50 of 0.23 μM in cell-free assays, 60-fold selective for DNA-PK than PI3K and inactive against both ATM and ATR. This compound enhances G2/M cell arrest and apoptosis.	Nucleic Acids Res, 2025, 53(11)gkaf468 Nucleic Acids Res, 2025, 53(18)gkaf961 Redox Biol, 2025, 80:103504
S8843	AZD7648	AZD7648 is a potent inhibitor of DNA-PK with an IC50 of 0.6 nM in biochemical assay and more than 100-fold selective against 396 other kinases.	Nat Commun, 2025, 16(1):3103 Nat Commun, 2025, 16(1):1140 Cell Rep Med, 2025, 6(7):102202
S8045	KU-0060648	KU-0060648 is a dual inhibitor of DNA-PK and PI3Kα, PI3Kβ, PI3Kδ with IC50 of 8.6 nM and 4 nM, 0.5 nM, 0.1 nM respectively, less inhibition of PI3Kγ with IC50 of 0.59 μM.	Breast Cancer Res, 2022, 24(1):41 Biomedicines, 2021, 9(5)579 Chembiochem, 2021, 22(12):2177-2181
S7891	CC-115	CC-115 is a dual inhibitor of DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) with IC50 values of 0.013 μM and 0.021 μM, respectively. It has potential antineoplastic activity.	Cell Rep Med, 2025, 6(7):102202 Nat Commun, 2024, 15(1):2625 Cells, 2024, 13(4)304
S8586	Nedisertib (M3814)	Nedisertib (M3814, Peposertib, MSC2490484A) is an orally bioavailable, highly potent and selective inhibitor of DNA activated protein kinase (DNA-PK) with an IC50 of < 3 nM.	Nat Genet, 2025, 57(5):1132-1141 Nat Commun, 2025, 16(1):6123 Cell Rep Med, 2025, 6(7):102202
S8379	YU238259	YU238259 is a novel inhibitor of homology-dependent DNA repair(HDR), but does not inhibit non-homologous end-joining (NHEJ), in cell-based GFP reporter assays.	Theranostics, 2023, 13(3):1130-1149 Int J Mol Sci, 2020, 21(16)E5821
S8427	LTURM34	LTURM34 is a specific DNA-PK inhibitor, 170-fold more selective for DNA-PK activity compared to PI3K activity, with IC50 value of 0.034 μM.	Front Oncol, 2023, 13:1287444 Int J Mol Sci, 2021, 22(19)10512
S6506	Compound 401	Compound 401 is a synthetic inhibitor of DNA-PK(IC50=0.28 μM) and mTOR (IC50=5.3 μM). It has no inhibition on p110α/p85α PI3K (>100 μM) and blocks the phosphorylation of S6 kinase 1 Thr389 and Akt Ser473 in COS7 cells.	Free Radic Biol Med, 2024, 224:831-845
S8593	VX-984	VX-984 (M9831) is an orally active, potent, selective, and ATP-competitive inhibitor of DNA-PK. This compound effectively suppresses non-homologous end joining (NHEJ) and increases DNA double-strand breaks (DSBs). It enhances the cytotoxic effects of ionizing radiation (IR) in various cancer cell lines, including non-small cell lung cancer (NSCLC) cell lines, in vitro. Additionally, this inhibitor reduces DNA-PKcs autophosphorylation.
S1105	LY294002	LY294002 (SF 1101, NSC 697286) is the first synthetic molecule known to inhibit PI3Kα/δ/β with IC50 of 0.5 μM/0.57 μM/0.97 μM, respectively; more stable in solution than Wortmannin, and also blocks autophagosome formation. It not only binds to class I PI3Ks and other PI3K-related kinases, but also to novel targets seemingly unrelated to the PI3K family. This compound also inhibits CK2 with IC50 of 98 nM. It is a non-specific DNA-PKcs inhibitor and activates autophagy and apoptosis.	Gut, 2025, gutjnl-2025-335163 Cell Mol Immunol, 2025, 22(5):541-556 Nat Commun, 2025, 16(1):1661
S2758	Wortmannin (SL-2052)	Wortmannin is the first described PI3K inhibitor with IC50 of 3 nM in a cell-free assay, with little selectivity within the PI3K family. Wortmannin blocks autophagosome formation and potently inhibits DNA-PK/ATM with IC50 of 16 nM and 150 nM in cell-free assays. Wortmannin also inhibits PLK1 activity.	Nat Commun, 2025, 16(1):1313 EMBO J, 2025, 10.1038/s44318-025-00507-z EMBO Mol Med, 2025, 10.1038/s44321-025-00222-6
S1038	PI-103	PI-103 is a multi-targeted PI3K inhibitor for p110α/β/δ/γ with IC50 of 2 nM/3 nM/3 nM/15 nM in cell-free assays, less potent to mTOR/DNA-PK with IC50 of 30 nM/23 nM. This compound induces apoptosis in murine T-cell Lymphoma.	Nat Commun, 2025, 16(1):4828 Cell Rep, 2025, 44(5):115675 Genes (Basel), 2025, 16(8)892
S2871	T0070907	T0070907 is a potent inhibitor of PPARγ (peroxisome proliferator activator receptor γ ) that induces G2/M arrest and enhances the effect of radiation in human cervical cancer cells through mitotic catastrophe. It also acts as an antagonist of PPARγ that suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms.	Nucleic Acids Res, 2025, 53(14)gkaf669 Cell Rep Med, 2025, 6(10):102373 Apoptosis, 2025, 30(5-6):1391-1409
S2817	Torin 2	Torin 2 is a potent and selective mTOR inhibitor with IC50 of 0.25 nM in p53−/− MEFs cell line; 800-fold greater selectivity for mTOR than PI3K and improved pharmacokinetic properties. This compound inhibits ATM/ATR/DNA-PK with EC50 of 28 nM/35 nM/118 nM,in PC3 cell lines respectively. It decreases cell viability and induces autophagy and apoptosis.	J Med Virol, 2025, 97(8):e70534 J Gen Virol, 2025, 106(3)002086 bioRxiv, 2025, 2025.09.24.678136
S1205	PIK-75 HCl	PIK-75 HCl is a p110α inhibitor with IC50 of 5.8 nM (200-fold more potently than p110β), isoform-specific mutants at Ser773, and also potently inhibits DNA-PK with IC50 of 2 nM in cell-free assays.	Proc Natl Acad Sci U S A, 2025, 122(13):e2426929122 Mol Oncol, 2024, 10.1002/1878-0261.13716 Cancers (Basel), 2024, 16(2)370
S8322	Samotolisib (LY3023414)	Samotolisib (LY3023414, GTPL8918) is an oral ATP competitive inhibitor of the class I PI3K isoforms, mTOR and DNA-PK.	Elife, 2025, 13RP95952 Mol Oncol, 2024, 10.1002/1878-0261.13703 Cancers (Basel), 2024, 16(20)3520
S2622	PP121	PP-121 is a multi-targeted inhibitor of PDGFR, Hck, mTOR, VEGFR2, Src and Abl with IC50 of 2 nM, 8 nM, 10 nM, 12 nM, 14 nM and 18 nM, also inhibits DNA-PK with IC50 of 60 nM.	Life Sci Alliance, 2021, 4(2)e202000882 PLoS One, 2016, 11(10):e0164895 PLoS One, 2016, 11(10):e0164895
S8589	SF2523	SF2523 is a highly selective and potent inhibitor of PI3K with IC50 values of 34 nM, 158 nM, 9 nM, 241 nM and 280 nM for PI3Kα, PI3Kγ, DNA-PK, BRD4 and mTOR, respectively.	Mol Ther Nucleic Acids, 2023, 31:309-323 Cell Biol Int, 2022, 10.1002/cbin.11833 Oncotarget, 2017, 8(58):98471-98481
S2638	NU7441 (KU-57788)	NU7441 (KU-57788) is a highly potent and selective DNA-PK inhibitor with IC50 of 14 nM. It also inhibits mTOR and PI3K with IC50 of 1.7 μM and 5 μM in cell-free assays, respectively, and reduces the frequency of NHEJ while increasing the rate of HDR following Cas9-mediated DNA cleavage.	Nat Cell Biol, 2025, 27(1):59-72 Trends Biotechnol, 2025, S0167-7799(25)00314-2 Nat Commun, 2025, 16(1):997
S2893	NU7026	NU7026 (LY293646) is a potent DNA-PK inhibitor with IC50 of 0.23 μM in cell-free assays, 60-fold selective for DNA-PK than PI3K and inactive against both ATM and ATR. This compound enhances G2/M cell arrest and apoptosis.	Nucleic Acids Res, 2025, 53(11)gkaf468 Nucleic Acids Res, 2025, 53(18)gkaf961 Redox Biol, 2025, 80:103504
S8843	AZD7648	AZD7648 is a potent inhibitor of DNA-PK with an IC50 of 0.6 nM in biochemical assay and more than 100-fold selective against 396 other kinases.	Nat Commun, 2025, 16(1):3103 Nat Commun, 2025, 16(1):1140 Cell Rep Med, 2025, 6(7):102202
S8045	KU-0060648	KU-0060648 is a dual inhibitor of DNA-PK and PI3Kα, PI3Kβ, PI3Kδ with IC50 of 8.6 nM and 4 nM, 0.5 nM, 0.1 nM respectively, less inhibition of PI3Kγ with IC50 of 0.59 μM.	Breast Cancer Res, 2022, 24(1):41 Biomedicines, 2021, 9(5)579 Chembiochem, 2021, 22(12):2177-2181
S7891	CC-115	CC-115 is a dual inhibitor of DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) with IC50 values of 0.013 μM and 0.021 μM, respectively. It has potential antineoplastic activity.	Cell Rep Med, 2025, 6(7):102202 Nat Commun, 2024, 15(1):2625 Cells, 2024, 13(4)304
S8586	Nedisertib (M3814)	Nedisertib (M3814, Peposertib, MSC2490484A) is an orally bioavailable, highly potent and selective inhibitor of DNA activated protein kinase (DNA-PK) with an IC50 of < 3 nM.	Nat Genet, 2025, 57(5):1132-1141 Nat Commun, 2025, 16(1):6123 Cell Rep Med, 2025, 6(7):102202
S8379	YU238259	YU238259 is a novel inhibitor of homology-dependent DNA repair(HDR), but does not inhibit non-homologous end-joining (NHEJ), in cell-based GFP reporter assays.	Theranostics, 2023, 13(3):1130-1149 Int J Mol Sci, 2020, 21(16)E5821
S8427	LTURM34	LTURM34 is a specific DNA-PK inhibitor, 170-fold more selective for DNA-PK activity compared to PI3K activity, with IC50 value of 0.034 μM.	Front Oncol, 2023, 13:1287444 Int J Mol Sci, 2021, 22(19)10512
S6506	Compound 401	Compound 401 is a synthetic inhibitor of DNA-PK(IC50=0.28 μM) and mTOR (IC50=5.3 μM). It has no inhibition on p110α/p85α PI3K (>100 μM) and blocks the phosphorylation of S6 kinase 1 Thr389 and Akt Ser473 in COS7 cells.	Free Radic Biol Med, 2024, 224:831-845
S8593	VX-984	VX-984 (M9831) is an orally active, potent, selective, and ATP-competitive inhibitor of DNA-PK. This compound effectively suppresses non-homologous end joining (NHEJ) and increases DNA double-strand breaks (DSBs). It enhances the cytotoxic effects of ionizing radiation (IR) in various cancer cell lines, including non-small cell lung cancer (NSCLC) cell lines, in vitro. Additionally, this inhibitor reduces DNA-PKcs autophosphorylation.
S1105	LY294002	LY294002 (SF 1101, NSC 697286) is the first synthetic molecule known to inhibit PI3Kα/δ/β with IC50 of 0.5 μM/0.57 μM/0.97 μM, respectively; more stable in solution than Wortmannin, and also blocks autophagosome formation. It not only binds to class I PI3Ks and other PI3K-related kinases, but also to novel targets seemingly unrelated to the PI3K family. This compound also inhibits CK2 with IC50 of 98 nM. It is a non-specific DNA-PKcs inhibitor and activates autophagy and apoptosis.	Gut, 2025, gutjnl-2025-335163 Cell Mol Immunol, 2025, 22(5):541-556 Nat Commun, 2025, 16(1):1661
S2758	Wortmannin (SL-2052)	Wortmannin is the first described PI3K inhibitor with IC50 of 3 nM in a cell-free assay, with little selectivity within the PI3K family. Wortmannin blocks autophagosome formation and potently inhibits DNA-PK/ATM with IC50 of 16 nM and 150 nM in cell-free assays. Wortmannin also inhibits PLK1 activity.	Nat Commun, 2025, 16(1):1313 EMBO J, 2025, 10.1038/s44318-025-00507-z EMBO Mol Med, 2025, 10.1038/s44321-025-00222-6
S1038	PI-103	PI-103 is a multi-targeted PI3K inhibitor for p110α/β/δ/γ with IC50 of 2 nM/3 nM/3 nM/15 nM in cell-free assays, less potent to mTOR/DNA-PK with IC50 of 30 nM/23 nM. This compound induces apoptosis in murine T-cell Lymphoma.	Nat Commun, 2025, 16(1):4828 Cell Rep, 2025, 44(5):115675 Genes (Basel), 2025, 16(8)892
S2871	T0070907	T0070907 is a potent inhibitor of PPARγ (peroxisome proliferator activator receptor γ ) that induces G2/M arrest and enhances the effect of radiation in human cervical cancer cells through mitotic catastrophe. It also acts as an antagonist of PPARγ that suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms.	Nucleic Acids Res, 2025, 53(14)gkaf669 Cell Rep Med, 2025, 6(10):102373 Apoptosis, 2025, 30(5-6):1391-1409
S2817	Torin 2	Torin 2 is a potent and selective mTOR inhibitor with IC50 of 0.25 nM in p53−/− MEFs cell line; 800-fold greater selectivity for mTOR than PI3K and improved pharmacokinetic properties. This compound inhibits ATM/ATR/DNA-PK with EC50 of 28 nM/35 nM/118 nM,in PC3 cell lines respectively. It decreases cell viability and induces autophagy and apoptosis.	J Med Virol, 2025, 97(8):e70534 J Gen Virol, 2025, 106(3)002086 bioRxiv, 2025, 2025.09.24.678136
S1205	PIK-75 HCl	PIK-75 HCl is a p110α inhibitor with IC50 of 5.8 nM (200-fold more potently than p110β), isoform-specific mutants at Ser773, and also potently inhibits DNA-PK with IC50 of 2 nM in cell-free assays.	Proc Natl Acad Sci U S A, 2025, 122(13):e2426929122 Mol Oncol, 2024, 10.1002/1878-0261.13716 Cancers (Basel), 2024, 16(2)370
S8322	Samotolisib (LY3023414)	Samotolisib (LY3023414, GTPL8918) is an oral ATP competitive inhibitor of the class I PI3K isoforms, mTOR and DNA-PK.	Elife, 2025, 13RP95952 Mol Oncol, 2024, 10.1002/1878-0261.13703 Cancers (Basel), 2024, 16(20)3520
S2622	PP121	PP-121 is a multi-targeted inhibitor of PDGFR, Hck, mTOR, VEGFR2, Src and Abl with IC50 of 2 nM, 8 nM, 10 nM, 12 nM, 14 nM and 18 nM, also inhibits DNA-PK with IC50 of 60 nM.	Life Sci Alliance, 2021, 4(2)e202000882 PLoS One, 2016, 11(10):e0164895 PLoS One, 2016, 11(10):e0164895
S8589	SF2523	SF2523 is a highly selective and potent inhibitor of PI3K with IC50 values of 34 nM, 158 nM, 9 nM, 241 nM and 280 nM for PI3Kα, PI3Kγ, DNA-PK, BRD4 and mTOR, respectively.	Mol Ther Nucleic Acids, 2023, 31:309-323 Cell Biol Int, 2022, 10.1002/cbin.11833 Oncotarget, 2017, 8(58):98471-98481

Signaling Pathway Map

DNA-dependent protein kinase (DNA-PK) is composed of three key components including two DNA-binding subunits Ku70 and Ku80 (Ku86), as well as one DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Based on protein sequence similarity, DNA-PK belongs to the phosphatidylinositol-3-kinase (PI3K) family, whereas, DNA-PK is not known to phosphorylate lipids and is therefore called PI3K-like kinase (PI3KK). The carboxyl-terminal region of Ku70 contains a SAP domain that is believed to be involved in chromosomal organization. The carboxyl-terminal region of Ku80 is required for the Ku70 and Ku80 heterodimer interaction with DNA-PKcs. The Ku heterodimer can bind to a variety of double-stranded end structures, including blunt ends, overhangs are the 3' or 5' end, and covalently closed hairpin ends. Like ATM and ATR, DNA-PKcs is structurally similar as it contains carboxyl-terminal domains, a large amino-terminal domain in addition to FAT and FATC domains flanking the kinase domain. The DNA-PKcs structure contains a channel large enough to accommodate double-stranded DNA, while the structure of Ku heterodimer is an asymmetric open ring, allowing the DNA to pass through the center. DNA-PKcs is one of the largest kinases identified to date, and it is the only kinase that is absolutely dependent on DNA binding for activity. DNA-PK has a strong preference for phosphorylating Serine (Ser) and Threonine (Thr) residues that are followed by glutamine or, less commonly, a hydrophobic residue. [1][2]

DNA-PK is involved in the ligation step of the non-homologous end joining (NHEJ) pathway required for DNA double-stranded break (DSB) repair, V(D)J recombination and telomere stabilization. A heterodimer of Ku70 and Ku80 initially binds to the double-stranded DNA broken ends and translocates inwards in an ATP-independent manner and recruits DNA-PKcs. This results in the stabilization of the protein/DNA binding and enabling NHEJ to proceed. Moreover, DNA-PKcs acts as a scaffold protein by joining two broken DNA ends together in a complex containing two DNA-PKcs molecules that contributes to the synapsis of the broken DNA ends and the localization of DNA repair proteins such as DNA ligase IV/XRCC4 complex to the site of damage. DNA-PK is activated in cis by the DNA to which it is bound, and stimulated by Ku heterodimer as well as the interaction of two molecules of DNA-PKcs, while end-bridging through synapsis is required for full kinase activation. DNA-PKcs autophosphorylation at multiple sites, including Thr2609 and Ser2056, results in an inactivation of DNA-PK kinase activity and NHEJ ability. To ensure NHEJ can proceed efficiently, DNA-PK phosphorylates and activates the Werner syndrome protein (WRN) to remove 3' phosphate or 3' phosphoglycolate groups generated following IR, and the nuclease Artemis to remove 5' overhangs and shorten 3' overhangs. In addition, DNA-PK promotes processing of hairpin DNA structures in V(D)J recombination by activation of Artemis. Cells that lack DNA-PKcs are acutely radiosensitive and have defective DSB repair, while mice lacking DNA-PKcs remain viable but are immunodeficient (due to the absence of immune development) as a result of accumulated processed DNA intermediates. Additionally, DNA-PK has been strongly implicated in telomere maintenance. DNA-PKcs-/- mice display significant telomeric fusion events consistent with the role of DNA-PKcs in telomere maintenance. Furthermore, DNA-PK is involved in the modulation of transcription by phosphorylation of RNA polymerases including pol I and pol II through its kinase activity, thereby regulating the function of these enzymes. By direct p53 phosphorylation, the modification of Ku70 releasing Bax, or suppressing the expression of p21, DNA-PK plays a significant role in mediating a p53-dependent apoptotic response under a range of cellular conditions including exposure to ionizing radiation (IR), environmental carcinogens and chemotherapeutic agents or in cells that have critically shortened telomeres. ^[1][2]

Specific inhibitors of DNA-PK used to selectively reduce NHEJ activity have been shown to be effective as single-agent therapies in homologous recombination (HR) -defective tumors. Treatment with a flavone-based DNA-PK inhibitor IC87361 leads to tumor regression. The inhibitors of DNA-PK such as NU7441 enhance the cytotoxicity of physical and chemical agents, leading to reduced clonogenic survival and cellular proliferation, as well as increased apoptosis, regardless of p53 status. Moreover, DNA-PK inhibitors combined with other DNA-damage response (DDR) inhibitors enhance the therapeutic potential of anticancer agents. ^[3][4]