渗透剂(生化)
化学
药物发现
综合应力响应
肌萎缩侧索硬化
激活剂(遗传学)
药理学
神经科学
神经退行性变
生物化学
疾病
生物
翻译(生物学)
内科学
医学
有机化学
受体
信使核糖核酸
基因
作者
Robert A. Craig,Javier de Vicente,Anthony A. Estrada,Jianwen Feng,Katrina W. Lexa,Mark J. Canet,William E. Dowdle,Rebecca I. Erickson,Brittany Flores,Patrick C. G. Haddick,Lesley A. Kane,Joseph W. Lewcock,Nathan J. Moerke,Suresh B. Poda,Zachary K. Sweeney,Ryan Takahashi,Vincent Tong,Jing Wang,Ernie Yulyaningsih,Hilda Solanoy
标识
DOI:10.1021/acs.jmedchem.3c02422
摘要
Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.
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