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]。