Double leucine zipper kinase (DLK, MAP3K12) and leucine zipper Carrying kinase (LZK, MAP3K13) are two homologous mitogen-activated protein kinases. They are regulators of neuronal apoptosis and axon degradation. And also they regulate the c-Jun N-terminal kinase (JNK) pathway. Specifically, DLK can lead to the phosphorylation of MKK4/7 and JNK-2/3 and c-Jun, resulting in pro-degradation (/pro-regeneration) transcription reactions. DLK knockout protects the central nervous system in neurodegenerative diseases. Meanwhile, LZK plays a synergistic role with DLK, to exert significant neuroprotection in the context of knockout. Both of them can be used in studies of Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). Here we will introduce a potent dual inhibitor of DLK and LZK, DN-1289.

DN-1289 selectively inhibits DLK and LZK with oral activity.

From: Siu M, et al. J Med Chem. 2018 Sep 27;61(18):8078-8087.

DN-1289 targets to DLK and LZK with IC₅₀s of 17 nM and 40 nM, respectively. It shows neuroprotection by inhibiting axon degeneration and caspases activation in dorsal root ganglion (DRG) neurons. DN-1289 (0.1-1 μM, 0-20 h) blocks axon degeneration dose-dependently induced by nerve growth factor (NGF) withdrawal. Moreover, it (0.1-1 μM, 0-20 h) inhibits NGF withdrawal induced-activation of caspases in DRG neurons over time.

As for in vivo efficacy, DN-1289 (10 mg/kg, 150 mg/kg, p.o., single dose) has good oral bioavailability and blood-brain permeability in mice. DN-1289 (150 mg/kg, p.o., b.i.d. for 10 d) inhibits c-Jun phosphorylation in a mouse model of optic nerve compression (ONC). Moreover, it (100 mg/kg, i.p., q.d. for 5 d) reverses DLK activation and reduces the expression of transcripts associated with DLK pathway activation in SOD1G93A mice.

In summary, DN-1289 is a potent dual DLK/LZK inhibitor. It has good oral absorption and brain permeability. It shows a neuroprotective effect by inhibiting DLK pathway activation and axon degeneration.

Reference:

[1] Craig RA 2nd, et al. J Med Chem. 2022 Dec 22;65(24):16290-16312.