Robert A Craig, Javier De Vicente, Anthony A Estrada, Jianwen A Feng, Katrina W Lexa, Mark J Canet, William E Dowdle, Rebecca I Erickson, Brittany N Flores, Patrick C G Haddick, Lesley A Kane, Joseph W Lewcock, Nathan J Moerke, Suresh B Poda, Zachary Sweeney, Ryan H Takahashi, Vincent Tong, Jing Wang, Ernie Yulyaningsih, Hilda Solanoy, Kimberly Scearce-Levie, Pascal E Sanchez, Liwei Tang, Musheng Xu, Rui Zhang, Maksim Osipov
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...
March 21, 2024: Journal of Medicinal Chemistry