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

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.

Remyelination protects neurons from DLK-mediated neurodegeneration

“…To determine if DLK-mediated signaling is necessary for driving the activation of downstream c -Jun signaling and apoptosis in the nuclei following chronic demyelination, we treated Myrf ΔiSox10 mice with the DLK inhibitor GNE-3511 61,62 . GNE-3511 was administered at 10 weeks post tamoxifen for three consecutive days via oral gavage (Figure 6A).…”

“…Given inhibiting DLK activity blocks apoptosis of demyelinated neurons, DLK activity is a strong candidate for neuroprotection in demyelinating disease. While there are a number of blood-brain barrier permeable inhibitors already produced 61,62 , a recent phase one trial with a DLK inhibitor in ALS warrants caution on this approach as prolonged DLK inhibition was associated with considerable safety concerns 86 . It may be necessary to dissect and target the downstream responses induced by DLK that drive ne urodegeneration in the context of remyelination failure to produce druggable therapeutic targets.…”

“…While DLK is critical for neurodegeneration following traumatic injury 29,37,65 , growth factor withdrawal 34 and in several rodent models of neurodegenerative disease 36 , it has not been previously implicated in demyelinating disease. To determine whether DLK is necessary for neurodegeneration following remyelination failure, we treated Myrf ΔiSox10 mice with the DLK inhibitor GNE-3511 66,67 at ten weeks post tamoxifen for three consecutive days via oral gavage (Figure 6A). We found this regimen increased serum levels of GNE-3511 above 2 µM.…”

Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy

“…In recent years, Genentech reported compound 1 (GNE-3511) and subsequently 2 (GNE-8505) (Figure ) as potent and selective inhibitors of DLK with good DMPK properties, in vivo efficacy, and CNS penetration. − In addition, GDC-0134 ( 3 ) was advanced into the clinic to treat ALS, although its development was halted due to an unacceptable safety profile and concerns over its long half-life and highly variable dose-exposure relationship . Recently, Denali reported DN1289 ( 4 ), an extremely close structural analogue of compound 3 …”

“…12 Recently, Denali reported DN1289 ( 4), an extremely close structural analogue of compound 3. 13 ■ RESULTS AND DISCUSSION…”