Gene Expression-Based Screen for Parkinson's Disease Identifies GW8510 as a Neuroprotective Agent.
We carried out a gene expression-based in silico screen in order to identify small molecules with gene-expression profiles that are anticorrelated with a gene-expression profile for Parkinson's disease (PD). We identified the cyclin-dependent kinase 2/5 (CDK2/5) inhibitor GW8510 as our most significant hit and characterized its effects in rodent MN9D cells and in human neuronal cells derived from induced pluripotent stem cells. GW8510 demonstrated neuroprotective ability in MN9D cells in the presence of 1-methyl-4-phenylpyridium (MPP(+)), a widely used neurotoxin model for Parkinson's disease. In order to delineate the nature and extent of GW8510's neuroprotective properties, we studied GW8510 in human neuronal cells in the context of various mechanisms of cellular stress. We found that GW8510 was protective against small-molecule mitochondrial and endoplasmic reticulum stressors. Our findings illustrate an approach to using small-molecule gene expression libraries to identify compounds with therapeutic potential in human diseases.
Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.|Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital , Boston, Massachusetts 02114, United States.|Program in Neuroscience, Harvard Medical School , Boston, Massachusetts 02115, United States.
Nivanthika K
NK
Wimalasena
Department of Science and Mathematics, National Technical Institute for the Deaf, Rochester Institute of Technology , Rochester, New York 14623, United States.
Viet Q
VQ
Le
Department of Chemistry, Wichita State University , Wichita, Kansas 67260, United States.
Kandatege
K
Wimalasena
Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.|Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
Stuart L
SL
Schreiber
Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.|Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital , Boston, Massachusetts 02114, United States.|Schizophrenia and Bipolar Disorder Program, Harvard Medical School and McLean Hospital , Belmont, Massachusetts 02478, United States.
Rakesh
R
Karmacharya
D000818:Animals; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D058953:Neural Stem Cells / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009498:Neurotoxins / Q000633:toxicity
C500810:GW8510; D007211:Indoles; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018844:Cyclin-Dependent Kinases
GW8510; Parkinson’s disease; iPSC; induced pluripotent stem cells; neural progenitor cells; neuroprotection