DNA-PK Inhibitors

Övrigt PI3K/Akt/mTOR Inhibitorer

• Utvalda inhibitorer
• Inhibitorer (19)

Kat.nr.	Produktnamn	Information	Citeringar av produktanvändning	Produktvalideringar
S8586	Nedisertib (M3814)	Nedisertib (M3814, Peposertib, MSC2490484A) är en oralt biotillgänglig, högeffektiv och selektiv hämmare av DNA activated protein kinase (DNA-PK) med ett IC50-värde på < 3 nM.	Int J Biol Macromol, 2026, 363:152219 Cells, 2026, 15(5)457 Nat Genet, 2025, 57(5):1132-1141
S8843	AZD7648	AZD7648 är en potent hämmare av DNA-PK med ett IC50-värde på 0,6 nM i biokemiska analyser och mer än 100 gånger högre selektivitet mot 396 andra kinaser.	bioRxiv, 2026, nan Nat Commun, 2025, 16(1):3103 Nat Commun, 2025, 16(1):1140
S2638	NU7441 (KU-57788)	NU7441 (KU-57788) är en mycket potent och selektiv DNA-PK-hämmare med IC50 på 14 nM. Den hämmar även mTOR och PI3K med IC50 på 1,7 μM respektive 5 μM i cellfria analyser, och minskar frekvensen av NHEJ samtidigt som den ökar hastigheten av HDR efter Cas9-medierad DNA-klyvning.	Autophagy, 2026, 1-27. Photochem Photobiol, 2026, 10.1111/php.70079 Nat Cell Biol, 2025, 27(1):59-72
S8045	KU-0060648	KU-0060648 är en dubbel hämmare av DNA-PK och PI3Kα, PI3Kβ, PI3Kδ med IC50 på 8,6 nM respektive 4 nM, 0,5 nM, 0,1 nM, mindre hämning av PI3Kγ med IC50 på 0,59 μM.	Oncotarget, October 11, 2016, 67235-67250 Molecular Cancer Therapeutics, February 01, 2018, 419-431 Molecular Cancer Therapeutics, February 01 2018, 419-431
S8593	VX-984	VX-984 (M9831) är en oralt aktiv, potent, selektiv och ATP-kompetitiv hämmare av DNA-PK. Denna förening undertrycker effektivt non-homologous end joining (NHEJ) och ökar DNA-dubbelsträngsbrott (DSBs). Den förstärker de cytotoxiska effekterna av joniserande strålning (IR) i olika cancercellinjer, inklusive icke-småcellig lungcancer (NSCLC)-cellinjer, in vitro. Dessutom reducerar denna hämmare autofosforylering av DNA-PKcs.
S1105	LY294002	LY294002 (SF 1101, NSC 697286) är den första syntetiska molekyl som är känd för att hämma PI3Kα/δ/β med IC50 på 0,5 μM/0,57 μM/0,97 μM, respektive; mer stabil i lösning än Wortmannin, och blockerar också autofagosombildning. Den binder inte bara till klass I PI3Ks och andra PI3K-relaterade kinaser, utan också till nya mål som verkar vara orelaterade till PI3K-familjen. Denna förening hämmar också CK2 med IC50 på 98 nM. Den är en icke-specifik DNA-PKcs-hämmare och aktiverar autophagy och apoptosis.	Research (Wash D C), 2026, 9:1190 Cell Prolif, 2026, 59(3):e70108 EMBO Rep, 2026, 27(5):1270-1300
S2817	Torin 2	Torin 2 är en potent och selektiv mTOR-hämmare med IC50 på 0,25 nM i p53−/− MEFs cellinje; 800 gånger större selektivitet för mTOR än PI3K och förbättrade farmakokinetiska egenskaper. Denna förening hämmar ATM/ATR/DNA-PK med EC50 på 28 nM/35 nM/118 nM, i PC3-cellinjer respektive. Den minskar cellviabilitet och inducerar autophagy och apoptosis.	PLoS Pathog, 2026, 22(3):e1014020 J Med Virol, 2025, 97(8):e70534 J Gen Virol, 2025, 106(3)002086
S2893	NU7026	NU7026 (LY293646) är en potent DNA-PK-hämmare med en IC50 på 0,23 μM i cellfria analyser, 60 gånger selektivare för DNA-PK än PI3K och inaktiv mot både ATM och ATR. Denna förening förstärker G2/M-cellarrest och apoptos.	Nat Commun, 2026, 17(1)3123 Nucleic Acids Res, 2025, 53(11)gkaf468 Nucleic Acids Res, 2025, 53(18)gkaf961
S7891	CC-115	CC-115 är en dubbel hämmare av DNA-beroende proteinkinas (DNA-PK) och mammalian target of rapamycin (mTOR) med IC50-värden på 0,013 μM respektive 0,021 μM. Det har potentiell antineoplastisk aktivitet.	Cell Rep Med, 2025, 6(7):102202 Nat Commun, 2024, 15(1):2625 Cells, 2024, 13(4)304
S8379	YU238259	YU238259 är en ny hämmare av homologi-beroende DNA-reparation (HDR), men hämmar inte icke-homolog sammankoppling (NHEJ), i cellbaserade GFP-reporteranalyser.	Biomolecules, August 6, 2025, 1132 International Journal of Molecular Sciences, August 13, 2020, 5821 Biomolecules, 2025, 1132
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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]