Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
Eur J Med Chem. 2024 Nov 5;277:116781. doi: 10.1016/j.ejmech.2024.116781. Epub 2024 Aug 15.
Ataxia-telangiectasia mutated (ATM) was first discovered in patients with AT (ataxia telangiectasia), which is characteristic with cerebellar degeneration, immunodeficiency, being susceptible to malignant tumors and sensitive to radiation. ATM kinase could detect DNA double-strand breaks and play a vital role in the DNA damage response. Inhibiting the function of ATM could sensitize tumor cells to both ionizing radiation (IR) and chemotherapy, as well as improve the chemoresistance and radioresistance observed in some patients. As such, ATM is a novel and important target for the cancer therapy. We reviewed ATM inhibitors reported in the last two decades, focusing on their development process, structure-activity relationships, inhibitory efficacy, pharmacokinetics and pharmacodynamics characteristics in the preclinical and clinical studies. We summarized the clinical value of ATM inhibitors in tumors and some neurodegenerative diseases, as well as the main challenges to the development of the drugs, providing directions and references for the future development of ATM inhibitors.
共济失调毛细血管扩张突变基因 (ATM) 最初在共济失调毛细血管扩张症 (ataxia telangiectasia，AT) 患者中被发现，AT 的特征是小脑退行性变、免疫缺陷、易患恶性肿瘤和对辐射敏感。ATM 激酶可以检测 DNA 双链断裂，并在 DNA 损伤反应中发挥重要作用。抑制 ATM 的功能可以使肿瘤细胞对电离辐射 (IR) 和化疗更加敏感，并提高一些患者中观察到的化疗耐药性和放疗耐药性。因此，ATM 是癌症治疗的一个新的重要靶点。我们回顾了过去二十年中报道的 ATM 抑制剂，重点关注它们的开发过程、结构-活性关系、在临床前和临床研究中的抑制效果、药代动力学和药效学特征。我们总结了 ATM 抑制剂在肿瘤和一些神经退行性疾病中的临床价值，以及药物开发的主要挑战，为未来 ATM 抑制剂的发展提供了方向和参考。
