A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS.
Cell Stem Cell
; 12(6): 713-26, 2013 Jun 06.
Article
en En
| MEDLINE
| ID: mdl-23602540
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Serina-Treonina Quinasas
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Glucógeno Sintasa Quinasa 3
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Péptidos y Proteínas de Señalización Intracelular
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Inhibidores de Proteínas Quinasas
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Células Madre Embrionarias
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Células Madre Pluripotentes Inducidas
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Esclerosis Amiotrófica Lateral
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Neuronas Motoras
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Stem Cell
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos