DNA-dependent kinase (DNA-PK) is a nuclear serine/threonine protein kinase complex that is a key component of the non-homologous end joining (NHEJ) process. DNA-PK plays an important role in the cellular response to DNA damage through the detection and repair of DNA double strand breaks (DSB). AZD7648 is a potent inhibitor of DNA-PK (0.6 nM in biochemical assay, 89 nM in A549 cells). AZD7648 inhibits ionising radiation (IR)-induced DNA-PK S2056 auto phosphoryalation with an IC50 of 92 nM in A549 non-small cell lung cancer (NSCLC) cells. In A549 cells, AZD7648 (≥1 µM) in combination with 2Gy IR for 48 hours led to a significant accumulation of cells arrested in the G2/M of the cell cycle, a 4-fold increase in micronuclei formation, and 3-fold induction of γH2AX, pATM S1981 and 53BP1 foci formation compared with IR alone. In vivo the combination of AZD7648 with IR (5x 2Gy) induced tumour regression in H1299 and A549 NSCLC xenografts in a dose-dependent manner (84 and 11% regression respectively). Similarly, liposomal doxorubicin (2.5 mg/kg weekly) in combination with AZD7648 (37.5 mg/kg bid) induced tumour regressions in the BT474c ER+ breast cancer xenograft model and in a TNBC PDX model (63% and 33% regression respectively).
AZD-7648 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HeLa cells
1 mM
1 hour
To study the binding mode of AZD-7648 with DNA-PKcs, revealing its mechanism of competitive inhibition of ATP binding
Nature. 2022 Jan;601(7894):643-648.
A549 non-small cell lung cancer cells
0.6 nM
1 hour
Evaluate the inhibitory effect of AZD7648 on DNA-PKcs autophosphorylation
Nat Commun. 2019 Nov 7;10(1):5065.
OAW42 ovarian cancer cells
3 µM
16 hours
Evaluate the effect of AZD7648 in combination with doxorubicin on DNA damage and apoptosis
Nat Commun. 2019 Nov 7;10(1):5065.
HNSCC cell lines (FaDu, A253, Detroit 562, UMSCC12, UMSCC74A, UMSCC6)
1 µM
1-hour pretreatment
AZD-7648 significantly reduced clonogenic survival of HNSCC cell lines, particularly following X-ray and proton beam therapy. DER (dose enhancement ratio) ranged from 1.41–2.86 (X-rays) and 1.63–2.52 (proton beam).
Cell Death Discov. 2024 Jun 12;10(1):282.
MC38 cells
1 µM
24 hours
To evaluate the radiosensitizing effect of AZD7648 on MC38 cells. Results showed that AZD7648 at 1 μmol/L significantly enhanced IR-induced cell death, with a DEF37 of 2.02.
Clin Cancer Res. 2021 Aug 1;27(15):4353-4366.
HSPCs (hematopoietic stem and progenitor cells)
7 µM
24 hours
Enhance HDR editing efficiency, reduce NHEJ, and increase the conversion rate of -175T>C and -158C>T in HSPCs
Stem Cell Res Ther. 2024 Dec 31;15(1):504.
Human airway basal stem cells (ABCs)
0.5 µM
24 hours
To evaluate the effect of AZD7648 on gene insertion efficiency, results showed AZD7648 significantly improved gene insertion efficiency (from 34.8% to 61.3%)
Mol Ther Nucleic Acids. 2024 Sep 16;35(4):102339.
UM-SCC-47
5 µM
24 hours
Evaluate the radiosensitizing effect of AZD7648 on HPV+ HNSCC cells, showing significant increase in G2/M arrest and cell death.
Cells. 2024 Feb 6;13(4):304.
CAL33
5 µM
24 hours
Evaluate the radiosensitizing effect of AZD7648 on HNSCC cells, showing significant inhibition of IR-induced DNA double-strand break repair and increased cell death.
Cells. 2024 Feb 6;13(4):304.
Cal78
1, 3, 10 µM
24 hours
Pretreatment with AZD7648 significantly enhanced the inhibitory effect of X-ray and carbon ion irradiation on cell proliferation, leading to G2/M phase cell cycle arrest.
Int J Mol Sci. 2024 Jun 4;25(11):6179.
SW-1353
1, 3, 10 µM
24 hours
Pretreatment with AZD7648 significantly enhanced the inhibitory effect of X-ray and carbon ion irradiation on cell proliferation, leading to G2/M phase cell cycle arrest.
Int J Mol Sci. 2024 Jun 4;25(11):6179.
HEL
50-200 µM
24-72 hours
To evaluate the effect of AZD-7648 on HEL cell density and viability. Results showed IC50 between 150-200 µM after 24 hours, decreasing to 97.7 µM and 85.5 µM after 48 and 72 hours, respectively.
Int J Mol Sci. 2023 Oct 18;24(20):15331.
LAMA-84
100-200 µM
24-72 hours
To evaluate the effect of AZD-7648 on LAMA-84 cell density and viability. Results showed IC50 values of 92.6 µM and 81.6 µM after 48 and 72 hours, respectively.
Int J Mol Sci. 2023 Oct 18;24(20):15331.
K-562
10-200 µM
24-72 hours
To evaluate the effect of AZD-7648 on K-562 cell density and viability. Results showed that IC50 was not reached (IC50 > 200 µM) within the tested concentration range.
Int J Mol Sci. 2023 Oct 18;24(20):15331.
Primary human CD4+ T cells
1 µM
3 days
Evaluate the effect of AZD7648 on CRISPR/Cas9-mediated HDR-KI efficiency, results showed significant increase in HDR-KI efficiency
Nat Commun. 2023 Aug 14;14(1):4761.
HiPSC
1 µM
3 days
Evaluate the effect of AZD7648 on CRISPR/Cas9-mediated HDR-KI efficiency, results showed significant increase in HDR-KI efficiency
Nat Commun. 2023 Aug 14;14(1):4761.
HepG2
1 µM
3 days
Evaluate the effect of AZD7648 on CRISPR/Cas9-mediated HDR-KI efficiency, results showed significant increase in HDR-KI efficiency
Nat Commun. 2023 Aug 14;14(1):4761.
Jurkat
1 µM
3 days
Evaluate the effect of AZD7648 on CRISPR/Cas9-mediated HDR-KI efficiency, results showed significant increase in HDR-KI efficiency
Nat Commun. 2023 Aug 14;14(1):4761.
HEK293T
1 µM
3 days
Evaluate the effect of AZD7648 on CRISPR/Cas9-mediated HDR-KI efficiency, results showed significant increase in HDR-KI efficiency
Nat Commun. 2023 Aug 14;14(1):4761.
Mature B-cell lines (3301015, 5680001)
1-20 µM
3 days
Evaluate AZD7648 effects on normal B-cell viability; results showed AZD7648 decreased viability of one or both B-cell lines at 1-20μM
Front Cell Dev Biol. 2023 Mar 31;11:1134121.
B-ALL cell lines (LAX56, BLQ5, LAX7R)
1-20 µM
3 days
Evaluate AZD7648 effects on B-ALL cell viability; results showed AZD7648 decreased viability at all tested concentrations
Front Cell Dev Biol. 2023 Mar 31;11:1134121.
MG63 cells
10 µM
48 hours
Evaluate the synergistic effect of AZD-7648 with DOX, results showed AZD-7648 significantly enhanced the inhibitory effect of DOX on osteosarcoma cells.
Cancer Res. 2024 Sep 4;84(17):2873-2887.
U2OS cells
10 µM
48 hours
Evaluate the synergistic effect of AZD-7648 with DOX, results showed AZD-7648 significantly enhanced the inhibitory effect of DOX on osteosarcoma cells.
Cancer Res. 2024 Sep 4;84(17):2873-2887.
HOS cells
10 µM
48 hours
Evaluate the synergistic effect of AZD-7648 with DOX, results showed AZD-7648 significantly enhanced the inhibitory effect of DOX on osteosarcoma cells.
Cancer Res. 2024 Sep 4;84(17):2873-2887.
143B cells
10 µM
48 hours
Evaluate the synergistic effect of AZD-7648 with DOX, results showed AZD-7648 significantly enhanced the inhibitory effect of DOX on osteosarcoma cells.
Cancer Res. 2024 Sep 4;84(17):2873-2887.
Primary human hematopoietic stem and progenitor cells (HSPCs)
0.5 µM
48 hours
Improving homology-directed repair (HDR) efficiency, achieving mean editing efficiency of 97%
Elife. 2024 Jun 3;12:RP91288.
Healthy fibroblasts (SBLF8, SBLF9)
5000 nM
48 hours
AZD7648 alone had minimal toxicity to healthy fibroblasts, but combined with ionizing radiation reduced clonogenic survival
Int J Mol Sci. 2024 May 22;25(11):5629.
HNSCC cell lines (Cal33)
5000 nM
48 hours
AZD7648 combined with ionizing radiation significantly increased cell death with supra-additive effects
Int J Mol Sci. 2024 May 22;25(11):5629.
B2M gene-targeted CD34+ HSPCs
0.33, 1, and 3 µM
48 hours
To evaluate the effect of AZD7648 on NHEJ and HDR, results showed AZD7648 inhibited NHEJ and promoted HDR.
To evaluate the effect of AZD-7648 on KG-1 cell density and viability. Results showed IC50 of 159.9 µM after 72 hours.
Int J Mol Sci. 2023 Oct 18;24(20):15331.
GOT1
1 µM
5 days
To evaluate the effect of AZD7648 on PRRT-induced cell death, results showed that AZD7648 significantly increased PRRT-induced cell death.
Theranostics. 2023 May 21;13(10):3117-3130.
NCI-H69
1 µM
7 days
To evaluate the effect of AZD7648 on the viability of PRRT-treated cells, results showed that AZD7648 significantly reduced the viability of PRRT-treated cells.
Theranostics. 2023 May 21;13(10):3117-3130.
BON1-SSTR2
1 µM
7 days
To evaluate the effect of AZD7648 on the viability of PRRT-treated cells, results showed that AZD7648 significantly reduced the viability of PRRT-treated cells.
Theranostics. 2023 May 21;13(10):3117-3130.
EW8 cells
0.1 µM
72 hours
AZD-7648 synergized with etoposide, significantly reducing cell viability and proliferation
Mol Cancer Ther. 2024 Aug 1;23(8):1109-1123.
TC-32 cells
0.1 µM
72 hours
AZD-7648 synergized with etoposide, significantly reducing cell viability and proliferation
Mol Cancer Ther. 2024 Aug 1;23(8):1109-1123.
FaDu head and neck cancer cells
0.6 µM
72 hours
Evaluate the effect of AZD7648 in combination with olaparib on genomic instability and apoptosis in ATM-deficient cells
Nat Commun. 2019 Nov 7;10(1):5065.
VMCUB-1
0.01–20 µM
72 hours
To evaluate the radiosensitizing effect of AZD7648 on bladder cancer cells, results showed a decrease in IC50 values with increasing radiation doses
Biomedicines. 2022 May 30;10(6):1277.
J82
0.01–20 µM
72 hours
To evaluate the radiosensitizing effect of AZD7648 on bladder cancer cells, results showed a decrease in IC50 values with increasing radiation doses
Biomedicines. 2022 May 30;10(6):1277.
SCaBER
0.01–20 µM
72 hours
To evaluate the radiosensitizing effect of AZD7648 on bladder cancer cells, results showed a decrease in IC50 values with increasing radiation doses
Biomedicines. 2022 May 30;10(6):1277.
AZD-7648 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NBSGW mice
Immune-deficient mouse model
Transplant after in vitro treatment
0.3 μM
16 weeks
To evaluate the effect of AZD7648 on long-term engraftment of HDR-edited HSPCs, results showed AZD7648 significantly increased the long-term engraftment of HDR-edited cells.
Evaluate the tumor growth inhibitory effect of AZD7648 in combination with radiotherapy
Nat Commun. 2019 Nov 7;10(1):5065.
Rj:NMRI-Foxn1nu/nu mice
BON1-SSTR2 and NCI-H69 xenograft models
Oral gavage
50 mg/kg or 100 mg/kg
Once daily for 7 consecutive days
To evaluate the enhancement of PRRT anti-tumor effects by AZD7648, results showed that AZD7648 significantly enhanced the anti-tumor effects of PRRT.
Theranostics. 2023 May 21;13(10):3117-3130.
NBSGW mice
Β-thalassemia and sickle cell disease model
Tail vein injection
7 μM
Single administration, observed for 16-18 weeks
Enhance HDR editing efficiency, reduce NHEJ, increase the conversion rate of -175T>C and -158C>T in HSPCs, and produce functional HbF in vivo
Stem Cell Res Ther. 2024 Dec 31;15(1):504.
BALB/c nude mice
Subcutaneous xenograft model
Oral
70 mg/kg
Once daily for 14 days
Evaluate the synergistic effect of AZD-7648 with DOX, results showed the combination therapy significantly inhibited osteosarcoma growth.
Cancer Res. 2024 Sep 4;84(17):2873-2887.
Mice
MC38, CT26, and B16-F10 syngeneic tumor models
Oral
75 mg/kg
Once daily for 5 days
To evaluate the antitumor efficacy of AZD7648 in combination with RT. Results showed that the combination of AZD7648 and RT significantly improved tumor control, with complete tumor regressions observed in 75% and 42% of mice in MC38 and CT26 models, respectively.
Clin Cancer Res. 2021 Aug 1;27(15):4353-4366.
Nude mice
TC-32 and EW8 orthotopic xenograft models
AZD-7648 orally, etoposide intraperitoneally
AZD-7648 25 mg/kg BID, etoposide 10 mg/kg daily
Daily for 5 days, repeated every 2 weeks
Combination of AZD-7648 and etoposide led to tumor shrinkage, enhanced DNA damage and apoptosis
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