Yang YM, Gupta SK, Kim KJ, Powers BE, Cerqueira A, Wainger BJ, Ngo HD, Rosowski KA, Schein PA, Ackeifi CA, Arvanites AC, Davidow LS, Woolf CJ, Rubin LL. A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Cell Stem Cell. 2013 Jun 06; 12(6):713-26.

Citation

Yang YM, Gupta SK, Kim KJ, Powers BE, Cerqueira A, Wainger BJ, Ngo HD, Rosowski KA, Schein PA, Ackeifi CA, Arvanites AC, Davidow LS, Woolf CJ, Rubin LL. 2013. 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. Pubmed: 23602540 DOI:S1934-5909(13)00139-2

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.

Related Faculty

Lee Rubin, Ph.D.

Rubin Lab

Lee Rubin investigates the key molecular mediators of different neurodegenerative diseases, with the ultimate goal of finding effective preclinical therapeutic candidates.