2. Academic Validation
  3. Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases

Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases

  • J Med Chem. 2024 Apr 11;67(7):5758-5782. doi: 10.1021/acs.jmedchem.3c02422.
Robert A Craig 2nd 1,  Javier De Vicente 1,  Anthony A Estrada 1,  Jianwen A Feng 1,  Katrina W Lexa 1,  Mark J Canet 1,  William E Dowdle 1,  Rebecca I Erickson 1,  Brittany N Flores 1,  Patrick C G Haddick 1,  Lesley A Kane 1,  Joseph W Lewcock 1,  Nathan J Moerke 1,  Suresh B Poda 1,  Zachary Sweeney 1,  Ryan H Takahashi 1,  Vincent Tong 1,  Jing Wang 1,  Ernie Yulyaningsih 1,  Hilda Solanoy 1,  Kimberly Scearce-Levie 1,  Pascal E Sanchez 1,  Liwei Tang 2,  Musheng Xu 2,  Rui Zhang 2,  Maksim Osipov 1
Affiliations

Affiliations

  • 1 Denali Therapeutics Inc., South San Francisco, California 94080, United States.
  • 2 Department of Chemistry, WuXi AppTec Co., Ltd., Tianjin 300457, China.
PMID: 38511649 DOI: 10.1021/acs.jmedchem.3c02422
Abstract

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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