title: A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS.
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.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Yin M
authors.initials: YM
authors.lastname: Yang
authors.forename: Shailesh K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Kim
authors.forename: Berit E
authors.initials: BE
authors.lastname: Powers
authors.forename: Antonio
authors.initials: A
authors.lastname: Cerqueira
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wainger
authors.forename: Hien D
authors.initials: HD
authors.lastname: Ngo
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Rosowski
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Schein
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Ackeifi
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Arvanites
authors.forename: Lance S
authors.initials: LS
authors.lastname: Davidow
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002783:Cholestenones / Q000737:chemistry / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D001552:Benzazepines; D002783:Cholestenones; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C000606290:SOD1 protein, human; C119620:kenpaullone; C522838:olesoxime; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3