Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the Ataxia telangiectasia and RAD3-related (ATR) kinase

The Ataxia telangiectasia and RAD3-related (ATR) kinase is a key regulator of the DNA replication stress responses and DNA-damage activated checkpoints. Several potent and selective ATR inhibitors are reported and four of them are currently in clinical trials in combination with radio- or chemotherapy. Based on the idea of degrading target proteins rather than inhibiting them, we designed, synthesized and biologically characterized a library of ATR-targeted proteolysis targeting chimera (PROTACs). Among the synthesized compounds, the lenalidomide-based PROTAC 42i (Abd110) was the most promising when tested in pancreatic cancer cells (MIA PaCa-2). It reduced ATR to 40 % of the levels in untreated cells. 42i (Abd110) selectively degraded ATR through the proteasome without affecting the associated kinases ATM and DNA-PKcs. 42i (Abd110) may be a promising candidate for further optimization and biological characterization in various cancer cells.