Journal of medicinal chemistry · 2024
Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Carroll Christopher L, Johnson Michael G, Ding Yanbing, Kang Zhijun, Vijayan R S K, Bardenhagen Jennifer P, Fang Cheng, Lapointe David, Li Meng, Liu Chiu-Yi, Lv Xiaobing, Ma XiaoYan, Pang Jihai, Shepard Hannah E, Suarez Catalina, Yau Anne Ju, Williams Christopher C, Wu Qi, Heald Robert A, Robinson Helen M R, Smith Graeme C M, Cross Jason B, Do Mary K Geck, Jiang Yongying, Lively Sarah, Yap Timothy A, Giuliani Virginia, Heffernan Timothy, Jones Philip, Di Francesco M Emilia
Аннотация
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.