Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers

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