Ataxia-telangiectasia mutated and Rad3-related kinases (ATM/ATR)

Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-related (ATR) kinases are central regulators of the DNA damage response (DDR) in eukaryotic cells [1, 2]. ATM is primarily recruited and activated by DNA double-strand breaks (DSBs) via the MRN complex, whereas ATR is activated by single-stranded DNA (ssDNA) coated with RPA, which typically occurs at stalled replication forks or as an intermediate in DSB repair [2, 3]. Once activated, these kinases phosphorylate a wide array of substrates, including Chk1, Chk2, and p53, to coordinate cell cycle checkpoints and facilitate DNA repair [1, 3]. In the context of oncology, ATM and ATR are significant therapeutic targets because many cancers harbor defects in specific DDR pathways, making them reliant on the remaining functional kinases for survival—a concept known as synthetic lethality [2, 4]. Small molecule inhibitors of ATM and ATR are currently being evaluated in clinical trials, both as monotherapies for tumors with specific genetic vulnerabilities (e.g., ATM-deficient or ARID1A-mutant cancers) and as sensitizing agents to enhance the efficacy of radiotherapy and DNA-damaging chemotherapeutics [4, 5].

Other names

ATMATRAtaxia-telangiectasia mutatedAtaxia-telangiectasia and Rad3-relatedPI3K-related kinase familyDDR kinasesSerine/threonine-protein kinase ATMSerine/threonine-protein kinase ATR

Inhibition of ATM or ATR kinase activity to disrupt DNA damage signaling, leading to impaired DNA repair, cell cycle progression, and induction of apoptosis, particularly in cells with pre-existing DDR deficiencies or under replication stress.