The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models.
The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models.
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DOI：
10.1126/sciadv.aat1719
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发表时间：
2018-06
期刊：
影响因子：
13.6
通讯作者：
Pass M
中科院分区：
文献类型：
--
作者：
Durant ST;Zheng L;Wang Y;Chen K;Zhang L;Zhang T;Yang Z;Riches L;Trinidad AG;Fok JHL;Hunt T;Pike KG;Wilson J;Smith A;Colclough N;Reddy VP;Sykes A;Janefeldt A;Johnström P;Varnäs K;Takano A;Ling S;Orme J;Stott J;Roberts C;Barrett I;Jones G;Roudier M;Pierce A;Allen J;Kahn J;Sule A;Karlin J;Cronin A;Chapman M;Valerie K;Illingworth R;Pass M
临床前数据强调 AZD1390 是一种潜在的强大新疗法，可增强脑肿瘤患者对放射治疗的反应。脑部肿瘤患者的生存率较低，原因是无法切除所有肿瘤组织（如果可手术）、化疗/靶向药物缺乏血脑屏障（BBB）渗透性以及肿瘤固有的放射/化疗耐药性。共济失调毛细血管扩张突变 (ATM) 蛋白协调细胞 DNA 损伤反应 (DDR)，以应对电离辐射 (IR) 诱导的细胞毒性 DNA 双链断裂。 ATM 基因消融或药物抑制导致肿瘤细胞对 IR 过敏。我们报告了临床级、极其有效（细胞IC50，0.78 nM）、高选择性[>10,000倍于同一磷脂酰肌醇3激酶相关激酶（PIKK）家族中的激酶]、口服生物可利用的ATM抑制剂AZD1390的主要药理学，该抑制剂专门针对血脑屏障渗透进行了优化，在食蟹猴脑部正电子发射断层扫描（PET）成像中得到证实微剂量 11C 标记的 AZD1390 (Kp,uu, 0.33)。 AZD1390 阻断 ATM 依赖性 DDR 通路活性，并与辐射结合诱导 G2 细胞周期期积累、微核和凋亡。 AZD1390 对神经胶质瘤和肺癌细胞系具有放射敏感性，p53 突变型神经胶质瘤细胞通常比野生型细胞具有更高的放射敏感性。在体内同基因和患者来源的神经胶质瘤以及原位肺脑转移模型中，与单独的 IR 治疗相比，AZD1390 与每日部分 IR（全脑或立体定向放射治疗）联合给药可显着诱导肿瘤消退并增加动物存活率。我们通过关联游离脑浓度、肿瘤磷酸-ATM/磷酸-Rad50 抑制、凋亡生物标志物（裂解的 caspase-3）诱导、肿瘤消退和生存，建立了药代动力学-药效-功效关系。根据此处提供的数据，AZD1390 目前正处于早期临床开发阶段，用作中枢神经系统恶性肿瘤的放射增敏剂。
Preclinical data highlight AZD1390 as a potentially powerful new therapy to enhance brain tumor patient responses to radiotherapy. Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase–related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11C-labeled AZD1390 (Kp,uu, 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies.
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影响因子：
14.8
作者：
Exell JC;Thompson MJ;Finger LD;Shaw SJ;Debreczeni J;Ward TA;McWhirter C;Siöberg CL;Martinez Molina D;Abbott WM;Jones CD;Nissink JW;Durant ST;Grasby JA
通讯作者：
Grasby JA
DOI：
10.1158/1078-0432.ccr-12-3408
发表时间：
2013-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Biddlestone-Thorpe L;Sajjad M;Rosenberg E;Beckta JM;Valerie NC;Tokarz M;Adams BR;Wagner AF;Khalil A;Gilfor D;Golding SE;Deb S;Temesi DG;Lau A;O'Connor MJ;Choe KS;Parada LF;Lim SK;Mukhopadhyay ND;Valerie K
通讯作者：
Valerie K
DOI：
10.1042/bj20131152
发表时间：
2014-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Banerjee S;Buhrlage SJ;Huang HT;Deng X;Zhou W;Wang J;Traynor R;Prescott AR;Alessi DR;Gray NS
通讯作者：
Gray NS
影响因子：
7.3
作者：
Di, Li;Rong, Haojing;Feng, Bo
通讯作者：
Feng, Bo
影响因子：
7
作者：
Bennetzen, Martin V.;Larsen, Dorthe Helena;Andersen, Jens S.
通讯作者：
Andersen, Jens S.