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.