title: Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models.
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.
authors.affiliation: Departments of †Discovery Chemistry, ‡Neurosciences, §Drug Metabolism and Pharmacokinetics, and ∥Biochemical and Cellular Pharmacology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Snahel
authors.initials: S
authors.lastname: Patel
authors.forename: Frederick
authors.initials: F
authors.lastname: Cohen
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Dean
authors.forename: Kelly
authors.initials: K
authors.lastname: De La Torre
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Estrada
authors.forename: Arundhati Sengupta
authors.initials: AS
authors.lastname: Ghosh
authors.forename: Paul
authors.initials: P
authors.lastname: Gibbons
authors.forename: Amy
authors.initials: A
authors.lastname: Gustafson
authors.forename: Malcolm P
authors.initials: MP
authors.lastname: Huestis
authors.forename: Claire E
authors.initials: CE
authors.lastname: Le Pichon
authors.forename: Han
authors.initials: H
authors.lastname: Lin
authors.forename: Wendy
authors.initials: W
authors.lastname: Liu
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.forename: Cuong Q
authors.initials: CQ
authors.lastname: Ly
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
authors.forename: Changyou
authors.initials: C
authors.lastname: Ma
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.forename: Young G
authors.initials: YG
authors.lastname: Shin
authors.forename: Hilda
authors.initials: H
authors.lastname: Solanoy
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Stark
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Xianrui
authors.initials: X
authors.lastname: Zhao
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lewcock
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D061985:Madin Darby Canine Kidney Cells; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D015394:Molecular Structure; D009410:Nerve Degeneration / Q000517:prevention & control*; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D047428:Protein Kinase Inhibitors; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12