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DNA-PK inhibiteurs (DNA-PK Inhibitors)

DNA-dependent protein kinase (DNA-PK) is a nuclear protein Serine (Ser)/Threonine (Thr) kinase that acts as both a molecular sensor and transmitter of DNA damage, and plays important roles in the DNA repair of double stranded breaks (DSBs), mediating immunoglobulin V(D)J gene recombination events, as well as telomere stabilization.  [show the full text]

Autre PI3K/Akt/mTOR Inhibiteurs

PI3K mTOR Akt GSK-3 ATM/ATR PDK AMPK PTEN MELK PI4K
N° Cat. Nom du produit Information Citations dutilisation du produit Validations de produits
S8586 Nedisertib (M3814) Le Nedisertib (M3814, Peposertib, MSC2490484A) est un inhibiteur hautement puissant et sélectif de la DNA activated protein kinase (DNA-PK), biodisponible par voie orale, avec une IC50 inférieure à 3 nM.
Nat Genet, 2025, 57(5):1132-1141
Nat Commun, 2025, 16(1):6123
Nat Commun, 2025, 16(1):7812
S8843 AZD7648 AZD7648 est un puissant inhibiteur de DNA-PK avec une IC50 de 0,6 nM dans un essai biochimique et plus de 100 fois plus sélectif contre 396 autres kinases.
Nat Commun, 2025, 16(1):3103
Nat Commun, 2025, 16(1):1140
Cell Rep Med, 2025, 6(7):102202
S2638 NU7441 (KU-57788) NU7441 (KU-57788) est un inhibiteur très puissant et sélectif de DNA-PK avec une IC50 de 14 nM. Il inhibe également mTOR et PI3K avec une IC50 de 1,7 μM et 5 μM respectivement dans des essais acellulaires, et réduit la fréquence de NHEJ tout en augmentant le taux de HDR après le clivage de l'ADN médiatisé par Cas9.
Nat Cell Biol, 2025, 27(1):59-72
Trends Biotechnol, 2025, S0167-7799(25)00314-2
Nat Commun, 2025, 16(1):997
Verified customer review of NU7441 (KU-57788)
S8045 KU-0060648 KU-0060648 est un double inhibiteur de DNA-PK et PI3Kα, PI3Kβ, PI3Kδ avec une IC50 de 8,6 nM et 4 nM, 0,5 nM, 0,1 nM respectivement, une inhibition moindre de PI3Kγ avec une IC50 de 0,59 μM.
Breast Cancer Res, 2022, 24(1):41
Biomedicines, 2021, 9(5)579
Chembiochem, 2021, 22(12):2177-2181
Verified customer review of KU-0060648
S8593 VX-984 VX-984 (M9831) est un inhibiteur oralement actif, puissant, sélectif et compétitif de l'ATP de la DNA-PK. Ce composé supprime efficacement la jonction des extrémités non homologues (NHEJ) et augmente les cassures double-brin de l'ADN (DSBs). Il améliore les effets cytotoxiques des rayonnements ionisants (IR) dans diverses lignées de cellules cancéreuses, y compris les lignées de cellules de cancer du poumon non à petites cellules (NSCLC), in vitro. De plus, cet inhibiteur réduit l'autophosphorylation de DNA-PKcs.
S1105 LY294002 Le LY294002 (SF 1101, NSC 697286) est la première molécule synthétique connue pour inhiber PI3Kα/δ/β avec des IC50 de 0,5 μM/0,57 μM/0,97 μM, respectivement ; plus stable en solution que la Wortmannine, et bloque également la formation d'autophagosomes. Il se lie non seulement aux PI3K de classe I et à d'autres kinases liées aux PI3K, mais aussi à de nouvelles cibles apparemment sans rapport avec la famille des PI3K. Ce composé inhibe également la CK2 avec une IC50 de 98 nM. C'est un inhibiteur non spécifique de la DNA-PKcs et il active l'autophagie et l'apoptose.
Gut, 2025, gutjnl-2025-335163
Cell Mol Immunol, 2025, 22(5):541-556
Nat Commun, 2025, 16(1):1661
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S2817 Torin 2 Torin 2 est un inhibiteur puissant et sélectif de mTOR avec une IC50 de 0,25 nM dans la lignée cellulaire p53 / - MEF ; sélectivité 800 fois supérieure pour mTOR par rapport à PI3K et propriétés pharmacocinétiques améliorées. Ce composé inhibe ATM/ATR/DNA-PK avec une EC50 de 28 nM/35 nM/118 nM,respectivement dans les lignées cellulaires PC3. Il diminue la viabilité cellulaire et induit l'autophagy et l'apoptosis.
J Med Virol, 2025, 97(8):e70534
J Gen Virol, 2025, 106(3)002086
bioRxiv, 2025, 2025.09.24.678136
Verified customer review of Torin 2
S2893 NU7026 NU7026 (LY293646) est un puissant inhibiteur de DNA-PK avec une IC50 de 0,23 μM dans les essais sans cellules, 60 fois plus sélectif pour DNA-PK que PI3K et inactif contre ATM et ATR. Ce composé améliore l'arrêt cellulaire G2/M et l'apoptose.
Nucleic Acids Res, 2025, 53(18)gkaf961
Nucleic Acids Res, 2025, 53(11)gkaf468
Redox Biol, 2025, 80:103504
Verified customer review of NU7026
S7891 CC-115 CC-115 est un double inhibiteur de la protéine kinase dépendante de l'ADN (DNA-PK) et de la cible de la rapamycine chez les mammifères (mTOR) avec des valeurs IC50 de 0,013 μM et 0,021 μM, respectivement. Il a une activité antinéoplasique potentielle.
Cell Rep Med, 2025, 6(7):102202
Nat Commun, 2024, 15(1):2625
Cells, 2024, 13(4)304
S8379 YU238259 YU238259 est un nouvel inhibiteur de la réparation de l'ADN dépendante de l'homologie (HDR), mais n'inhibe pas la jonction des extrémités non homologues (NHEJ), dans les essais rapporteurs GFP basés sur des cellules.
Theranostics, 2023, 13(3):1130-1149
Int J Mol Sci, 2020, 21(16)E5821

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]