Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models.

Snahel Patel, Frederick Cohen, Brian J Dean, Kelly De La Torre, Gauri Deshmukh, Anthony A Estrada, Arundhati Sengupta Ghosh, Paul Gibbons, Amy Gustafson, Malcolm P Huestis, Claire E Le Pichon, Han Lin, Wendy Liu, Xingrong Liu, Yichin Liu, Cuong Q Ly, Joseph P Lyssikatos, Changyou Ma, Kimberly Scearce-Levie, Young G Shin, Hilda Solanoy, Kimberly L Stark, Jian Wang, Bei Wang, Xianrui Zhao, Joseph W Lewcock, Michael Siu

文献索引：J. Med. Chem. 58(1) , 401-18, (2015)

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摘要

Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications.