Candidate drug for ALS

There is currently only one approved treatment for amyotrophic lateral sclerosis (ALS), and phase III trials for two new compounds recently failed. Thus, there is a substantial need to test potential new drugs with rigorous in vitro models before testing in the clinic. Now, Lee Rubin and colleagues report a small molecule screen in stem cell–derived motor neurons in which they identified the GSK-3 inhibitor kenpaullone as a candidate therapeutic for ALS (Cell Stem Cell 12, 713–726, 2013). The authors differentiated motor neurons from wild-type mouse embryonic stem cells (ESCs) and ESCs from mice carrying the SOD1^G93A human transgene. They screened a library of 5,000 small molecules and identified a number of compounds that improved survival of one or both types of motor neurons, including several kinase inhibitors. The authors further investigated kenpaullone, which reproducibly increased the survival of both wild-type and SOD1^G93A motor neurons. Other known GSK-3 inhibitors had weaker or no effect, suggesting that the effect of kenpaullone might be due to effects besides GSK-3 inhibition. Using an antibody array for phosphorylated kinases, the authors discovered that kenpaullone reduces the phosphorylation and activation of the JNK–c-Jun cell death pathway. Kenpaullone also promoted the survival of motor neurons differentiated from human ALS induced pluripotent stem cells.