AZD6738 is an orally active and highly selective ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor with an IC50 value of 1nM[1]. By blocking ATR kinase activity, AZD6738 inhibits the activation of the DNA damage repair checkpoint, thereby inducing tumor cell apoptosis and enhancing tumor cell sensitivity to chemotherapy and radiotherapy[2]. AZD6738 is used in research to explore the efficacy, mechanisms of action, and tolerability of both its monotherapy and its combination with DNA-damaging agents (such as cisplatin) in the treatment of conditions including ataxia telangiectasia mutated (ATM)-deficient non-small cell lung cancer and other diseases[3,4].
In vitro, treatment of sensitive SK-BR-3 cells with AZD6738 (0.1, 0.5, 1μM) for 5 days induced S-phase cell cycle arrest and increased the proportion of cells in the sub-G1 phase, accompanied by PARP cleavage and downregulation of Cyclin E expression[5]. Treatment of LoVo and HCC1806 cells with AZD6738 (1μM) for 24h significantly modulated ATR- and ATM-dependent signaling pathways and induced the expression of DNA damage response markers such as CHK1 pSer345, KAP1 pSer824, and γH2AX[6]. Treatment of H23, H460, and A549 cells with AZD6738 (1μM) for 24h inhibited CHK1 (S345) phosphorylation and p21/p27 expression, and induced DNA damage (γH2A.X) and apoptosis (PARP cleavage) in H23 and H460 cells[1].
In vivo, oral administration of AZD6738 (50mg/kg; once daily) to Balb/c nude mice bearing SNU-601 xenografts for 20 days significantly inhibited tumor growth without causing significant body weight loss[7]. Combination treatment with AZD6738 (25mg/kg; once daily; p.o.) and cisplatin in mice bearing ATM-deficient H23 xenografts for 14 days resulted in rapid tumor regression (84.8%) and achieved complete tumor disappearance in some mice[1].
References:
[1] VENDETTI F P, LAU A, SCHAMUS S, et al. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo[J]. Oncotarget, 2015, 6(42): 44289.
[2] JONES C D, BLADES K, FOOTE K M, et al. Discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients[J]. Cancer Research, 2013, 73(8_Supplement): 2348.
[3] NAM A R, JIN M H, PARK J E, et al. Therapeutic targeting of the DNA damage response using an ATR inhibitor in biliary tract cancer[J]. Cancer Research and Treatment, 2019, 51(3): 1167-1179.
[4] MEI L, ZHANG J, HE K, et al. Ataxia telangiectasia and Rad3-related inhibitors and cancer therapy: where we stand[J]. Journal of Hematology & Oncology, 2019, 12(1): 43.
[5] KIM H J, MIN A, IM S A, et al. Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells[J]. International Journal of Cancer, 2017, 140(1): 109-119.
[6] WILSON Z, ODEDRA R, WALLEZ Y, et al. ATR inhibitor AZD6738 (ceralasertib) exerts antitumor activity as a monotherapy and in combination with chemotherapy and the PARP inhibitor olaparib[J]. Cancer Research, 2022, 82(6): 1140-1152.
[7] MIN A, IM S A, JANG H, et al. AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM deficiency in gastric cancer cells[J]. Molecular Cancer Therapeutics, 2017, 16(4): 566-577.
AZD6738是一种具有口服活性和高效选择性的共济失调毛细血管扩张和Rad3相关蛋白（ATR）激酶抑制剂，IC50值为1nM[1]。AZD6738通过阻断ATR激酶活性，抑制DNA损伤修复检查点激活，从而诱导肿瘤细胞凋亡，并增强肿瘤细胞对化疗和放疗的敏感性[2]。AZD6738用于探索其单药或与DNA损伤药物（如cisplatin）联合使用，在治疗共济失调毛细血管扩张突变（ATM）缺陷型和非小细胞肺癌等疾病中的疗效，作用机制与耐受性的研究[3,4]。
在体外，AZD6738（0.1, 0.5, 1μM）处理敏感的SK-BR-3细胞5天，诱导S期细胞周期阻滞和sub-G1期细胞比例增加，并伴随PARP切割和Cyclin E表达下调[5]。AZD6738（1μM）处理LoVo和HCC1806细胞24h，显著调节了ATR和ATM依赖性信号通路，诱导了CHK1 pSer345、KAP1 pSer824和γH2AX等DNA损伤反应标志物的表达[6]。AZD6738（1μM）处理H23、H460和A549细胞24h，抑制了Chk1 (S345)磷酸化及p21/p27表达，并在H23和H460中引起DNA损伤（γH2A.X）和凋亡（PARP切割）[1]。
在体内，AZD6738（50mg/kg; once daily）口服治疗携带SNU-601异种移植瘤的Balb/c裸鼠20天，显著抑制了肿瘤的生长，且未引起明显的体重下降[7]。AZD6738（25mg/kg; once daily; p.o.）与cisplatin联合治疗携带ATM缺陷型的H23异种移植瘤小鼠14天，引起了肿瘤的快速消退（84.8%），并在部分小鼠中实现了肿瘤的完全消失[1]。