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.

journal_name

J Med Chem

authors

Patel S,Cohen F,Dean BJ,De La Torre K,Deshmukh G,Estrada AA,Ghosh AS,Gibbons P,Gustafson A,Huestis MP,Le Pichon CE,Lin H,Liu W,Liu X,Liu Y,Ly CQ,Lyssikatos JP,Ma C,Scearce-Levie K,Shin YG,Solanoy H,Stark KL,Wa

doi

10.1021/jm5013984

subject

Has Abstract

pub_date

2015-01-08 00:00:00

pages

401-18

issue

1

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

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