| Literature DB >> 25341110 |
Snahel Patel1, 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.
Abstract
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.Entities:
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Year: 2014 PMID： 25341110 DOI： 10.1021/jm5013984
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446