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

作者：Christopher L. Carroll, Michael G. Johnson, Yanbing Ding, Zhijun Kang, R. S. K. Vijayan, Jennifer Bardenhagen, Cheng Fang, David Lapointe, Meng Li, Chiu-Yi Liu, Xiaobing Lv, XiaoYan Ma, Jihai Pang, Hannah E. Shepard, Catalina Suarez, Anne Yau, Christopher C. Williams, Qi Wu, Robert A. Heald, Helen M.R. Robinson, Graeme C.M. Smith, Jason B. Cross, Mary Geck, Yongying Jiang, Sarah Lively, Timothy A. Yap, Virginia Giuliani, Timothy P. Heffernan, Philip Jones, Maria Emilia Di Francesco · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c01595 · 被引用次数：15 · 研究领域：DNA Repair Mechanisms、Cancer therapeutics and mechanisms、Cancer-related Molecular Pathways

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.