Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration Models

• Published in: Journal of medicinal chemistry Vol. 58; no. 1; pp. 401 - 418
• Main Authors: Patel, Snahel, Cohen, Frederick, Dean, Brian J., De La Torre, Kelly, Deshmukh, Gauri, Estrada, Anthony A., Ghosh, Arundhati Sengupta, Gibbons, Paul, Gustafson, Amy, Huestis, Malcolm P., Le Pichon, Claire E., Lin, Han, Liu, Wendy, Liu, Xingrong, Liu, Yichin, Ly, Cuong Q., Lyssikatos, Joseph P., Ma, Changyou, Scearce-Levie, Kimberly, Shin, Young G., Solanoy, Hilda, Stark, Kimberly L., Wang, Jian, Wang, Bei, Zhao, Xianrui, Lewcock, Joseph W., Siu, Michael
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.01.2015; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Discovery; HEK293 Cells; Humans; Life Sciences & Biomedicine; Madin Darby Canine Kidney Cells; MAP Kinase Kinase Kinases - antagonists & inhibitors; Mice, Inbred C57BL; Models, Chemical; Molecular Structure; Nerve Degeneration - prevention & control; Neurodegenerative Diseases - prevention & control; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Rats; Science & Technology; PATHWAYS; IN-VITRO; NEURONAL DEGENERATION; COUPLING REACTIONS; JNK; DRUG DISCOVERY; GANGLION-CELL DEATH; ARYL CHLORIDES; PARKINSONS-DISEASE; AXONAL INJURY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5013984

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.