2. Academic Validation
  3. Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis

Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis

  • J Med Chem. 2022 Dec 22;65(24):16290-16312. doi: 10.1021/acs.jmedchem.2c01056.
Robert A Craig 2nd 1,  Brian M Fox 1,  Cheng Hu 1,  Katrina W Lexa 1,  Maksim Osipov 1,  Arun P Thottumkara 1,  Martin Larhammar 1,  Takashi Miyamoto 1,  Anil Rana 1,  Lesley A Kane 1,  Ernie Yulyaningsih 1,  Hilda Solanoy 1,  Hoang Nguyen 1,  Roni Chau 1,  Timothy Earr 1,  Yuji Kajiwara 1,  Daniel Fleck 1,  Anthony Lucas 1,  Patrick C G Haddick 1,  Ryan H Takahashi 1,  Vincent Tong 1,  Jing Wang 1,  Mark J Canet 1,  Suresh B Poda 1,  Kimberly Scearce-Levie 1,  Ankita Srivastava 1,  Zachary K Sweeney 1,  Musheng Xu 2,  Rui Zhang 2,  Jianrong He 2,  Yanan Lei 2,  Zheng Zhuo 2,  Javier de Vicente 1
Affiliations

Affiliations

  • 1 Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, California 94080, United States.
  • 2 Department of Chemistry, WuXi AppTec Co., Ltd., 168 Nanhai Road, 10th Avenue, Tianjin TEDA, Tianjin 300457, China.
PMID: 36469401 DOI: 10.1021/acs.jmedchem.2c01056
Abstract

Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK. DN-1289 (14), a potent and selective dual DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life across species and is anticipated to freely penetrate the central nervous system with no brain impairment based on in vivo rodent pharmacokinetic studies and human in vitro transporter data. Proximal target engagement and disease relevant pathway biomarkers were also favorably regulated in an in vivo model of amyotrophic lateral sclerosis.

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