2. Academic Validation
  3. Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease

Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease

  • J Med Chem. 2017 Oct 12;60(19):8083-8102. doi: 10.1021/acs.jmedchem.7b00843.
Snahel Patel,  William J Meilandt,  Rebecca I Erickson,  Jinhua Chen 1,  Gauri Deshmukh,  Anthony A Estrada,  Reina N Fuji,  Paul Gibbons,  Amy Gustafson,  Seth F Harris,  Jose Imperio,  Wendy Liu,  Xingrong Liu,  Yichin Liu,  Joseph P Lyssikatos,  Changyou Ma 1,  Jianping Yin,  Joseph W Lewcock,  Michael Siu
Affiliations

Affiliation

  • 1 Department of Chemistry, WuXi AppTec Co., Ltd. , 288 Fute Zhonglu, Wai Gao Qiao Free Trade Zone, Shanghai 200131, P. R. China.
PMID: 28929759 DOI: 10.1021/acs.jmedchem.7b00843
Abstract

Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compounds, exemplified by inhibitor 14, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concentrations that exceed those required for DLK inhibition in the brain.

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