Ataxia telangiectasia and Rad3-related kinase (ATR) (ATR)

Ataxia telangiectasia and Rad3-related kinase (ATR) is a large serine/threonine-protein kinase belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family and serves as a master regulator of the DNA damage response (DDR) [1, 5, 11]. It is primarily activated by single-stranded DNA (ssDNA) coated with Replication Protein A (RPA), which typically accumulates at stalled replication forks or during the processing of various DNA lesions [11, 14]. Upon activation, ATR phosphorylates downstream effectors like CHK1 to trigger cell cycle checkpoints, stabilize replication forks, and promote DNA repair, thereby maintaining genomic integrity [6, 14]. In oncology, ATR has emerged as a high-priority therapeutic target because many cancer cells exhibit high levels of replication stress or defects in alternative DDR pathways, such as ATM loss, making them hypersensitive to ATR inhibition—a concept known as synthetic lethality [4, 9, 15]. Several potent and selective ATR inhibitors, such as ceralasertib and berzosertib, are currently in clinical development, both as monotherapies and in combination with DNA-damaging agents or PARP inhibitors [3, 4, 5]. While promising, the clinical use of ATR inhibitors is often limited by dose-dependent myelosuppression, necessitating careful patient selection using biomarkers like ATM deficiency or high replication stress [3, 4, 6]. Beyond its role in cancer, mutations in the ATR gene are associated with Seckel syndrome, a rare disorder characterized by primordial dwarfism and microcephaly [1, 11, 16]. The development of ATR inhibitors represents a significant advancement in precision medicine, aiming to exploit specific genetic vulnerabilities in tumors while sparing normal tissues [9, 15].

Other names

ATRATR serine/threonine kinaseAtaxia telangiectasia and Rad3-related proteinFRAP-related protein 1FRP1MEC1SCKLSCKL1FCTCS

ATR inhibition; specifically, small molecule inhibition of the ATR kinase domain prevents phosphorylation of downstream substrates like CHK1, leading to the collapse of stalled replication forks, accumulation of DNA double-strand breaks, and induction of apoptosis in cells with high replication stress or deficient alternative DNA repair pathways.