Ataxia-telangiectasia mutated (ATM) kinase (ATM)

Ataxia-telangiectasia mutated (ATM) kinase is a large serine/threonine protein kinase belonging to the phosphoinositide 3-kinase-related kinase (PIKK) family (UniProt P16473). It serves as a master regulator of the cellular response to DNA double-strand breaks (DSBs), which are among the most lethal forms of DNA damage (PubMed: 10802652). Upon the occurrence of DSBs, ATM is recruited to the damage site by the MRN complex, where it undergoes autophosphorylation and subsequently phosphorylates a wide array of substrates, including p53, CHK2, and H2AX, to initiate cell cycle arrest and DNA repair (PubMed: 28234359). Mutations in the ATM gene lead to Ataxia-telangiectasia, a rare genetic disorder characterized by cerebellar degeneration and increased cancer predisposition. In oncology, ATM is a high-priority therapeutic target because its inhibition can induce synthetic lethality in tumors with existing DNA repair deficiencies or sensitize cancer cells to radiotherapy and chemotherapy (PubMed: 31515461). SYH2051 is a potent and selective ATM inhibitor currently under clinical investigation for the treatment of advanced solid tumors (ClinicalTrials.gov: NCT05116124). By blocking ATM activity, SYH2051 prevents the repair of DNA damage, leading to the accumulation of genomic instability and eventual cell death in malignant cells. This therapeutic approach is particularly promising for patients with tumors harboring specific genetic vulnerabilities in the DNA damage response pathway.

Other names

ATMAT1ATAATCATDATEATDCTEL1TELO1Serine-protein kinase ATM

ATM kinase inhibition