Structural highlights
FunctionM3K12_HUMAN May be an activator of the JNK/SAPK pathway. Phosphorylates beta-casein, histone 1 and myelin basic protein in vitro. Publication Abstract from PubMedSignificant 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. Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease.,Patel S, Meilandt WJ, Erickson RI, Chen J, Deshmukh G, Estrada AA, Fuji RN, Gibbons P, Gustafson A, Harris SF, Imperio J, Liu W, Liu X, Liu Y, Lyssikatos JP, Ma C, Yin J, Lewcock JW, Siu M J Med Chem. 2017 Sep 20. doi: 10.1021/acs.jmedchem.7b00843. PMID:28929759[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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