AZD1390
目录号 : GC19468
AZD1390是一种新型选择性共济失调毛细血管扩张突变激酶抑制剂，能够高效穿透血脑屏障。
Cas No.:2089288-03-7
Sample solution is provided at 25 µL, 10mM.
_1-3.$$$39978408@51.jpg');)
_1-9.$$$38538795@65.jpg');)
_1-9.$$$39112701@51.jpg');)
_1-7.$$$37316672@70.jpg');)
_366-372.$$$36198801@70.jpg');)
.$$$38565142@65.jpg');)
_1867-1883.$$$33248023@67.jpg');)
_eads6055.$$$39977546@45.jpg');)
_eadm9805.$$$40080571@45.jpg');)
_eadj3020.$$$39666821@45.jpg');)
_1-20.$$$39757301@28.jpg');)
_1-24.$$$38898113@28.jpg');)
_273-287.$$$36806353@46.jpg');)
_1-16.$$$37156877@44.jpg');)
_1-19.$$$37460805@44.jpg');)
_1291-1307.$$$34518654@46.jpg');)
AZD1390 is a novel and selective ataxia-telangiectasia mutated (ATM) kinase inhibitor, distinguished by AZD1390 high efficiency in crossing the blood-brain barrier[1]. By inhibiting ATM kinase activity, AZD1390 blocks the repair signaling of DNA double-strand breaks, thereby enhancing the sensitivity of tumor cells to DNA damage induced by radiotherapy[2-3]. AZD1390 exhibits favorable oral bioavailability and brain distribution, positioning it as a promising clinical candidate for the treatment of central nervous system malignancies [4].
In vitro, pretreatment of head and neck squamous cell carcinoma (HNSCC) cell lines (such as FaDu and A253) with AZD1390 (10nM) for 1 hour, followed by X-ray (1–4Gy) or proton beam therapy (PBT) irradiation, significantly reduced clonogenic survival and inhibited the growth of 3D tumor spheroids[5]. In TP53-mutant glioblastoma cells (e.g., U251, GBM12, GBM43), pretreatment with AZD1390 (10–30nM) for 1 hour prior to X-ray irradiation (2.5–5Gy) synergistically decreased cell survival, induced apoptosis, abrogated G0–G1 phase arrest, increased G2/M phase retention, and led to persistent chromosomal instability and micronucleus formation [6].
In vivo, intraperitoneal administration of AZD1390 (5mg/kg) at 30 minutes, 24 hours, and 48 hours after reperfusion in a mouse model of middle cerebral artery occlusion (MCAO) significantly reduced cerebral infarct volume and improved neurological deficit scores (mNSS), rotarod latency, forelimb grip strength, and foot-fault test performance[7]. In a patient-derived xenograft (PDX) model of breast cancer central nervous system metastasis, oral administration of AZD1390 (20mg/kg) 1 hour before radiotherapy (2.5 Gy/day × 4 days) markedly suppressed the growth of HER2-positive (CM07, CM14) and triple-negative breast cancer (CM16) xenograft tumors[8].
References:
[1] Pike KG, Hunt TA, Barlaam B, et al. Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood-Brain Barrier: The Discovery of AZD1390. J Med Chem. 2024 Feb 22;67(4):3090-3111.
[2] Al-Zoubi RM, Garada K, Al Huneidi R, et al. ATM inhibitors in cancer radiotherapy: Mechanisms, clinical development, and future directions. Eur J Med Chem. 2025 Dec 15;300:118137.
[3] Qian C, Li X, Zhang J, et al. Small Molecular Inhibitors That Target ATM for Drug Discovery: Current Research and Potential Prospective. J Med Chem. 2024 Sep 12;67(17):14742-14767.
[4] Jin MH, Oh DY. ATM in DNA repair in cancer. Pharmacol Ther. 2019 Nov;203:107391.
[5] Fabbrizi MR, Doggett TJ, Hughes JR, et al. Inhibition of key DNA double strand break repair protein kinases enhances radiosensitivity of head and neck cancer cells to X-ray and proton irradiation. Cell Death Discov. 2024 Jun 12;10(1):282.
[6] Chen J, Laverty DJ, Talele S, et al. Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization. Sci Transl Med. 2024 Feb 14;16(734):eadj5962.
[7] Lan Z, Qu LJ, Liang Y, et al. AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury. CNS Neurosci Ther. 2024 Apr;30(4):e14696.
[8] Tew BY, Kalfa AJ, Yang Z, et al. ATM-Inhibitor AZD1390 Is a Radiosensitizer for Breast Cancer CNS Metastasis. Clin Cancer Res. 2023 Nov 1;29(21):4492-4503.
AZD1390是一种新型选择性共济失调毛细血管扩张突变激酶抑制剂，能够高效穿透血脑屏障[1]。AZD1390通过抑制ATM激酶的活性，从而阻断其对DNA双链断裂的修复信号传导，增强肿瘤细胞对放射治疗引发的DNA损伤的敏感性[2-3]。AZD1390具有优良的口服生物利用度和脑内分布特性，是治疗中枢神经系统恶性肿瘤的候选药物[4]。
在体外，AZD1390（10nM）预处理头颈部鳞状细胞癌（HNSCC）细胞系（FaDu、A253）1小时，随后进行X射线（1-4Gy）或质子束治疗（PBT）照射，AZD1390可显著降低细胞的克隆形成存活率并抑制3D肿瘤球的生长[5]。AZD1390（10-30nM）预处理TP53突变型胶质母细胞瘤细胞（U251、GBM12、GBM43）1小时，随后进行X射线照射（2.5-5Gy），AZD1390与辐射联合处理可协同降低细胞存活率，并显著诱导TP53突变型细胞凋亡，消除细胞G0-G1期阻滞，增加G2/M期滞留，并引发持续的染色体不稳定性和微核形成[6]。
在体内，AZD1390（5mg/kg）于小鼠大脑中动脉闭塞（MCAO）模型再灌注后30分钟、24小时和48小时腹腔注射，可显著降低脑梗死体积并改善神经功能缺损评分（mNSS）、转棒实验潜伏时间、前肢抓握力和足误测试表现[7]。AZD1390（20mg/kg）于乳腺癌中枢神经系统转移患者来源异种移植（PDX）模型小鼠中，在放射治疗（2.5Gy/天×4天）前1小时口服给药，可显著抑制HER2阳性（CM07、CM14）及三阴性乳腺癌（CM16）移植瘤的生长[8]。
| Cell experiment [1]: | |
Cell lines | FaDu, A253, Detroit 562, UMSCC12, UMSCC74A, and UMSCC6 cells (human head and neck squamous cell carcinoma cell lines) |
Preparation Method | Cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) or Modified Eagle Medium (MEM) supplemented with 10% fetal bovine serum (FBS), 2mM L-glutamine, penicillin-streptomycin, and non-essential amino acids at 37°C, 5% CO₂. Cells were pretreated with the AZD1390 (10nM) for 1 hour prior to irradiation. |
Reaction Conditions | 10nM; 1h pretreatment |
Applications | AZD1390 significantly decreased the clonogenic survival of cell following both X-ray and proton irradiation, with dose enhancement ratios. AZD1390 also reduced the growth of HNSCC cells grown as 3D spheroids, particularly in combination with radiation. |
| Animal experiment [2]: | |
Animal models | Female NOG mice (4- to 6-week-old) with subcutaneous breast cancer patient-derived xenograft (PDX) tumors (CM07, CM14, CM16) |
Preparation Method | Mice were administered AZD1390 (20mg/kg/day) by oral gavage for 4 days, 1 hour prior to each fraction of radiation therapy (2.5Gy/day for 4 days). Tumors were implanted subcutaneously in the flank, and treatment began when the average tumor volume reached 70mm³. |
Dosage form | 20mg/kg/day; oral gavage |
Applications | Pretreatment with AZD1390 followed by radiation therapy significantly inhibited tumor growth in all three PDX models compared to radiation alone. The combination therapy resulted in sustained tumor inhibition and improved animal survival. |
References: | |
| Cas No. | 2089288-03-7 | SDF | |
| 化学名 | 7-fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one | ||
| Canonical SMILES | FC(C=C(N=CC(N1C)=C2N(C(C)C)C1=O)C2=C3)=C3C(C=N4)=CC=C4OCCCN5CCCCC5 | ||
| 分子式 | C27H32FN5O2 | 分子量 | 477.57 |
| 溶解度 | DMSO : 5 mg/mL (10.47 mM; ultrasonic and warming and heat to 60°C) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.0939 mL | 10.4697 mL | 20.9393 mL |
| 5 mM | 418.8 μL | 2.0939 mL | 4.1879 mL |
| 10 mM | 209.4 μL | 1.047 mL | 2.0939 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet