Dual leucine zipper kinase (DLK, MAP3K12) activation of the JNK / c-Jun pathway in neurons is essential for stress-induced degeneration; thus, DLK presents an attractive therapeutic target for neurodegenerative diseases such as ALS.  Previously, we have disclosed a series of small molecule DLK inhibitors that effectively reduce c-Jun phosphorylation in acute injury mouse models (optic nerve crush and MPTP).  These inhibitors were important to our understanding of DLK inhibition in vivo.  Herein, we describe the discovery of a series of inhibitors with enhanced potency, PK, kinase selectivity, and tolerability.

Dual leucine zipper kinase inhibitors for the treatment of neurodegenerative diseases

253rd National Meeting (2017)

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