molecules of the month


selective, CNS-penetrant dual DLK/LZK inhibitor

neuroprotective effects for in vivo + in vitro models for ALS

LBDD/SBDD + opt.

J. Med. Chem., December 5, 2022

Denali Therapeutics, South San Fransisco, CA

DN-1289 chemical structure selective, CNS-penetrant dual DLK/LZK inhibitor - Denali Therapeutics, South San Fransisco, CA
2 mins read

What is it? DN-1289 is a CNS-penetrant, ATP-competitive DLK/LZK-selective dual kinase inhibitor intended to treat amyotrophic lateral sclerosis (ALS). The molecule is structurally closely related to Genentech’s recent Ph. I candidate, GDC-0134. Why do we care? Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are involved in both neurodegeneration and axon growth, and DLK in particular is a target of interest for neurodegenerative diseases including AD, Parkinson’s, and ALS.DLK regulates neuronal apoptosis through JNK kinase activation, and loss of DLK signaling has been shown to be neuroprotective in at least 12 different preclinical models. The leading DLK inhibitor in clinical development, Genentech’s GDC-0134, recently completed Ph. I trials (NCT03807739, NCT03237741, NCT02655614), with dosing up to 1200 mg daily.…

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