A Small Molecule Screen in Stem-Cell-Derived Motor Neurons Identifies a Kinase Inhibitor as a Candidate Therapeutic for ALS

作者：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^*

来源：Cell Stem Cell, 2013, 12(6): 713-726.

DOI：10.1016/j.stem.2013.04.003

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.

• 出版日期2013-6-6