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

Ataxia telangiectasia and Rad3-related protein (ATR) is a fundamental serine/threonine-protein kinase that acts as a primary sensor of DNA replication stress and single-stranded DNA breaks (UniProt: P20848). It belongs to the phosphoinositide 3-kinase-related kinase (PIKK) family and coordinates the DNA damage response (DDR) by phosphorylating downstream effectors like CHK1 to induce cell cycle arrest and facilitate DNA repair (PubMed: 28334994). This mechanism ensures genomic stability by preventing cells from entering mitosis with unrepaired DNA damage or collapsed replication forks. In the context of oncology, ATR is a significant therapeutic target because many cancer cells exhibit high levels of replication stress or lack alternative DDR pathways, such as ATM or p53, making them hypersensitive to ATR inhibition (PubMed: 31064780). Pharmacological inhibition of ATR, using agents like Berzosertib or Ceralasertib, can lead to replication catastrophe and cell death, especially when used in combination with chemotherapy or PARP inhibitors (ClinicalTrials.gov). This approach exploits the concept of synthetic lethality to selectively target tumor cells while sparing normal tissue to the extent possible.

Other names

ATRSerine/threonine-protein kinase ATRFRP1MEC1SCKLSCKL1

ATR inhibitors selectively bind to and inhibit the kinase activity of ATR, preventing the activation of the CHK1-mediated DNA damage checkpoint (PubMed: 24302555). This inhibition leads to the failure of cell cycle arrest and replication fork stabilization, resulting in the accumulation of DNA double-strand breaks and subsequent apoptosis, particularly in cells with high replication stress or other DNA repair deficiencies (PubMed: 31064780).