Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease, characterized by motor neuron (MN) death, for which there are no truly effective treatments. Here, we describe a new small molecule survival screen carried out using MNs from both wild-type and mutant SOD1 mouse embryonic stem cells. Among the hits we found, kenpaullone had a particularly impressive ability to prolong the healthy survival of both types of MNs that can be attributed to its dual inhibition of GSK-3 and HGK kinases. Furthermore, kenpaullone also strongly improved the survival of human MNs derived from ALS-patient-induced pluripotent stem cells and was more active than either of two compounds, olesoxime and dexpramipexole, that recently failed in ALS clinical trials. Our studies demonstrate the value of a stem cell approach to drug discovery and point to a new paradigm for identification and preclinical testing of future ALS therapeutics.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / drug therapy*
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Amyotrophic Lateral Sclerosis / enzymology
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Amyotrophic Lateral Sclerosis / pathology
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Animals
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Benzazepines / chemistry
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Benzazepines / pharmacology
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Cell Differentiation / drug effects
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Cell Survival / drug effects
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Cells, Cultured
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Cholestenones / chemistry
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Cholestenones / pharmacology
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Embryonic Stem Cells / cytology*
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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Indoles / chemistry
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Indoles / pharmacology
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Induced Pluripotent Stem Cells / cytology*
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Transgenic
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Motor Neurons / cytology*
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Motor Neurons / drug effects*
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Motor Neurons / enzymology
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Mutation
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Protein Kinase Inhibitors / analysis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Structure-Activity Relationship
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Superoxide Dismutase-1
Substances
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Benzazepines
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Cholestenones
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Indoles
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Intracellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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SOD1 protein, human
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kenpaullone
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olesoxime
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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MAP4K4 protein, human
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Protein Serine-Threonine Kinases
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Glycogen Synthase Kinase 3