Ataxia telangiectasia and Rad3-related protein (ATR) and Poly (ADP-ribose) polymerase (PARP) (ATR/PARP)

Ataxia telangiectasia and Rad3-related protein (ATR) and Poly (ADP-ribose) polymerase (PARP) are key enzymes in the DNA damage response (DDR) pathway, essential for maintaining genomic integrity (UniProt: Q13535, P09874). ATR is a kinase that senses replication stress and single-strand DNA breaks, while PARP1 is an enzyme that detects DNA damage and recruits repair machinery (PubMed: 33536590). The concept of a 'resistance-modifying payload' refers to the use of ATR or PARP inhibitors as the cytotoxic component of antibody-drug conjugates (ADCs). This strategy aims to deliver these potent DDR-disrupting agents directly to tumor cells, overcoming resistance to conventional therapies and minimizing systemic toxicity (AstraZeneca, 2022). By targeting these proteins, these therapies induce synthetic lethality, particularly in tumors with existing DNA repair deficiencies such as BRCA mutations (Nature Reviews Drug Discovery, 2021).

Other names

ATRPARPDDR inhibitorsDNA damage response proteinsResistance-modifying payloads

Inhibition of ATR and PARP enzymes to disrupt DNA damage repair and induce synthetic lethality, specifically delivered as payloads in antibody-drug conjugates to overcome resistance (PubMed: 33536590, 26473910).