A Small Molecule Screen in Stem-Cell-Derived Motor Neurons Identifies a Kinase Inhibitor as a Candidate Therapeutic for ALS
2013
Yang, Yin M. | Gupta, Shailesh K. | Kim, Kevin J. | Powers, Berit E. | Cerqueira, Antonio | Wainger, Brian J. | Ngo, Hien D. | Rosowski, Kathryn A. | Schein, Pamela A. | Ackeifi, Courtney A. | Arvanites, Anthony C. | Davidow, Lance S. | Woolf, Clifford J. | Rubin, Lee L.
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.
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