Definition

An orally bioavailable inhibitor of the DNA damage response (DDR) protein kinase ataxia telangiectasia and Rad3 related (ATR) kinase, with potential checkpoint inhibitory and antineoplastic activities. Upon oral administration, ATR inhibitor ATG-018 selectively targets and binds to ATR, and inhibits its activity and ATR-mediated signaling. This blocks the downstream phosphorylation of the serine/threonine protein kinase checkpoint kinase 1 (CHK1). This results in the inhibition of DNA damage checkpoint activation, the disruption of DNA damage repair, and the induction of tumor cell apoptosis. ATR, a serine/threonine protein kinase upregulated in a variety of cancer cell types, plays a key role in DNA repair, cell cycle progression and survival. It is activated by DNA damage caused during DNA replication-associated stress.