期刊
CELL CHEMICAL BIOLOGY
卷 26, 期 4, 页码 593-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2019.01.004
关键词
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资金
- NIH [NS095280, TL1 TR000441]
- Conrad N. Hilton Foundation Pilot Innovator in MS Award
- Mallinckrodt Foundation Grant Award
- Peterson family
- Fakhouri family
- Long family
- Goodman family
- Geller family
- Judge family
- Weidenthal family
- CWRU School of Medicine
- Case Comprehensive Cancer Center [P30 CA043703]
- [F30MH116581]
Small molecules that promote oligodendrocyte formation have been identified in drug repurposing screens to nominate candidate therapeutics for diseases in which myelin is lost, including multiple sclerosis. We recently reported that many such molecules enhance oligodendrocyte formation not by their canonical targets but by inhibiting a narrow range of enzymes in cholesterol biosynthesis. Here we identify enhancers of oligodendrocyte formation obtained by screening a structurally diverse library of 10,000 small molecules. Identification of the cellular targets of these validated hits revealed a majority inhibited the cholesterol biosynthesis enzymes CYP51, TM7SF2, or EBP. In addition, evaluation of analogs led to identification of CW3388, a potent EBP-inhibiting enhancer of oligodendrocyte formation poised for further optimization.
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