AZD0156 is a clinical candidate and selective ATM inhibitor with IC50 value of 5.7nM (>10,000 fold selectivity to ATM than ATR), possessing highly solubility and excellent preclinical pharmacokinetic properties. Co-administration of AZD0156 orally could potentiated the efficacy of both irinotecan (50mg/kg) in an SW620 xenograft model at dose of 20mg/kg, QD, for 2-4 weeks and olaparib (50mg/kg) in a HBCx-10 patient derived tumor xenograft model at dose of 5mg/kg, QD, for 1-3 weeks.
作用机制
AZD0156 interacts with the ATP binding site of ATM.[1]
AZD0156 细胞实验
Cell Line
Concentration
Treated Time
Description
References
U2OS cells
2 nM
1 hour
To assess cell sensitivity to proton treatment.
Cancer Res. 2021 Jun 15;81(12):3333-3346.
U251 ATRXKO cells
30 nM
1 hour
To evaluate the radiosensitization effect of AZD0156 on ATRX-deficient glioma cells, results showed that AZD0156 significantly enhanced the sensitivity of ATRX-deficient cells to radiation
Cell Rep. 2022 Jan 11;38(2):110216.
SJ-GBM2 cells
30 nM
1 hour
To evaluate the radiosensitization effect of AZD0156 on ATRX-deficient glioma cells, results showed that AZD0156 significantly enhanced the sensitivity of ATRX-deficient cells to radiation
Cell Rep. 2022 Jan 11;38(2):110216.
MOC2 cells
50 nM
24 hours
AZD0156 (50 nM) increased Ifnβ expression in MOC2 cells following 8 Gy RT.
J Immunother Cancer. 2023 Sep;11(9):e007474.
B78 cells
50 nM
24 hours
AZD0156 (50 nM) increased Ifnβ expression in B78 cells following 12 Gy RT.
J Immunother Cancer. 2023 Sep;11(9):e007474.
SCC6 cells
50 nM
24 hours
AZD0156 (50 nM) increased Ifnβ expression in SCC6 cells following 8 Gy RT.
J Immunother Cancer. 2023 Sep;11(9):e007474.
U251 ATRXKO cells
1 µM
4 hours
To evaluate the effect of AZD0156 on ATM inhibition in ATRX-deficient cells, results showed reduced levels of pATM and gH2AX.
Cell Rep. 2022 Jan 11;38(2):110216.
U251 ATRXKO cells
1 µM
4 hours
To evaluate the effect of AZD0156 on ATRX-deficient cells, results showed that AZD0156 inhibited ATM kinase activity.
Cell Rep. 2022 Jan 11;38(2):110216.
D54-ATMR cells
10 µM
70 minutes
To evaluate the effect of AZD0156 on the ATM inhibition reporter, results showed a sustained increase in ATM inhibition signal.
Cell Rep. 2022 Jan 11;38(2):110216.
D54-ATMR cells
10 µM and 10 nM
70 minutes
To evaluate the effect of AZD0156 and AZD1390 on ATM inhibition, results showed that AZD0156 and AZD1390 had a sustained inhibitory effect on ATM in vitro.
Cell Rep. 2022 Jan 11;38(2):110216.
TFK-1 cells
2 µM
8 hours
Inhibition of TET1 protein expression
Adv Sci (Weinh). 2024 Dec;11(47):e2407323.
EGI-1 cells
2 µM
8 hours
Inhibition of TET1 protein expression
Adv Sci (Weinh). 2024 Dec;11(47):e2407323.
U251 ATRXKO cells
30 nM
ATRX-deficient cells exhibited significant radiation sensitivity at 30 nM of AZD0156.
Cell Rep. 2022 Jan 11;38(2):110216.
ALT neuroblastoma cell lines
100 nM
To evaluate the sensitivity of AZD0156 to TMZ+SN-38, results showed that AZD0156 significantly enhanced the sensitivity of ALT neuroblastoma cell lines to TMZ+SN-38
Sci Transl Med. 2021 Aug 18;13(607):eabd5750.
Telomerase-positive neuroblastoma cell lines
100 nM
To evaluate the sensitivity of AZD0156 to TMZ+SN-38, results showed that telomerase-positive cell lines had a heterogeneous response to AZD0156
Sci Transl Med. 2021 Aug 18;13(607):eabd5750.
AZD0156 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Athymic nude mice
MC-BR-BTY-0030
Intraperitoneal injection
10 mg/kg
One hour prior to and 24 following irradiation
To enhance the efficacy of proton Bragg peak irradiation.
Cancer Res. 2021 Jun 15;81(12):3333-3346.
Mice
Balb/c nude mice
Oral
10 mg/kg
Enhanced efficacy of low-dose CFI-400945 when combined with AZD0156
Clin Cancer Res. 2024 Sep 3;30(17):3904-3918.
Mice
ATRX-deficient orthotopic murine brain tumor model
Intraperitoneal injection
10 mg/kg
3-4 times per week for 2 weeks
To evaluate the effect of ATM inhibitor AZD0156 on the survival of ATRX-deficient glioma mice, results showed that AZD0156 significantly extended the median survival of mice.
Cell Rep. 2022 Jan 11;38(2):110216.
Mice
ATRX-deficient orthotopic GBM model
Intraperitoneal injection
10 mg/kg
Every 3-4 days for two weeks
Combination treatment with AZD0156 and radiation significantly extended the survival of mice with ATRX-deficient GBM models.
Cell Rep. 2022 Jan 11;38(2):110216.
Mice
ATRX-deficient GBM neurosphere model
Intraperitoneal injection
10 mg/kg
4 times per week for 2 weeks
To evaluate the radiosensitizing effect of AZD0156 on ATRX-deficient tumors, results showed a significant increase in median survival.
Cell Rep. 2022 Jan 11;38(2):110216.
Mice
ATRX-deficient glioma model
Intraperitoneal injection
10 mg/kg
Every 3-4 days for two weeks, total of 4 treatments
To evaluate the therapeutic effect of AZD0156 on the ATRX-deficient glioma model, results showed that AZD0156 significantly extended the survival of mice
Cell Rep. 2022 Jan 11;38(2):110216.
C57BL/6 mice
MOC2 and B78 tumor models
Oral
10 mg/kg
Once daily for five consecutive days
Combination of AZD0156 with radiotherapy significantly suppressed tumor growth in MOC2 and B78 models and improved mouse survival.
J Immunother Cancer. 2023 Sep;11(9):e007474.
Mice
ALT neuroblastoma xenograft models
Oral
20 mg/kg
Once daily for 14 days
To evaluate the effect of AZD0156 in combination with TMZ+IRN, results showed that AZD0156 significantly extended event-free survival in ALT xenograft models
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