Progress of ATM inhibitors: opportunities and challenges

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.