Discovery of\nART0380,\na Potent and Selective ATR Kinase\nInhibitor Undergoing Phase 2 Clinical Studies for the Treatment of\nAdvanced or Metastatic Solid Cancers

One of the hallmarks of cancer is\nhigh levels of DNA replication\nstress and defects in the DNA damage response (DDR) pathways, which\nare critical for maintaining genomic integrity. Ataxia telangiectasia\nand Rad3-related protein (ATR) is a key regulator of the DDR machinery\nand an attractive therapeutic target, with multiple ATR inhibitors\nholding significant promise in ongoing clinical studies. Herein, we\ndescribe the discovery and characterization of ART0380 (<b>6</b>), a potent and selective ATR inhibitor with a compelling in vitro\nand in vivo pharmacological profile currently undergoing Phase 2 clinical\nstudies in patients with advanced or metastatic solid tumors as monotherapy\nand in combination with DNA-damaging agents (NCT04657068 and NCT05798611).\nART0380 (<b>6</b>) has a favorable human PK profile suitable\nfor both intermittent and continuous once-daily (QD) dosing, characterized\nby a dose-proportional increase in exposure and low variability.