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

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.